2-acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof

ABSTRACT

The invention relates to 2-acylamino-4-phenylthiazole derivatives of general formula (I): 
     
       
         
         
             
             
         
       
     
     pharmaceutically acceptable acid-addition salts thereof, hydrates or solvates of such derivatives or such pharmaceutically acceptable acid addition salts, intermediates thereto, processes for the preparation thereof, and therapeutic application thereof.

The present invention relates to 2-acylamino-4-phenylthiazolederivatives, to their preparation and to their therapeutic application.

The present invention relates to compounds corresponding to formula (I):

in which:

-   -   R₁ represents a hydrogen or halogen atom or a (C₁-C₄)alkyl,        trifluoroethyl, hydroxyl, (C₁-C₄) alkoxy, trifluoromethoxy,        trifluoroethoxy, (C₃-C₈)cycloalkyloxy, allyloxy,        cyclopropylmethoxy or (C₁-C₄)alkylthio group;    -   R₂ represents a hydrogen or halogen atom or a (C₁-C₈)alkyl,        trifluoroethyl, perfluoro(C₁-C₄)alkyl, (C₃-C₁₀)cycloalkyl,        phenyl, (C₁-C₈)alkoxy, trifluoromethoxy, trifluoroethoxy,        allyloxy, (C₃-C₈)cycloalkylmethoxy, (C₃-C₈)cycloalkyloxy or        (C₃-C₈) cycloalkylmethyl group;    -   R₃ represents a group chosen from:    -   a) a1) —O— (C₂-C₄)alk-A;        -   a2) —O— (C₁-C₄)alk-B;        -   a3) —O-E;    -   b) —(C₁-C₄)alk-A;    -   c) —B;    -   d) d1) —(C₁-C₄)alk-NR₄—(C₂-C₃)alk-A;        -   d2) —(C₁-C₄)alk-NR₄—(C₁-C₃)alk-B;    -   e) e1) —CONR₄—(C₂-C₄)alk-A;        -   e2) —CONR₄—(C₁-C₄)alk-B;        -   e3) —CONR₄-E;    -   f) f1) —CO-D-(C₁-C₂)alk-A;        -   f2) —CO-G-A;

-   -   R₄ represents a hydrogen atom or a (C₁-C₄)alkyl group;    -   A represents a group NR₅R₆;    -   B represents a group

-   -   D represents a group

-   -   E represents a group

-   -   G represents a group

-   -   —R₅ and R₆ each represent, independently of each other, a        hydrogen atom or a (C₁-C₆)alkyl, allyl,        (C₂-C₄)alk-O—(C₁-C₄)alkyl, (C₂-C₄)alk-OH, (C₁-C₃)alk-CON(R₄)₂,        (C₂-C₃) alk-NHCO—(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl,        (C₃-C₇)cycloalkylmethyl, —CO—(C₁-C₄)alkyl, pyrrolidinyl        optionally substituted with a —CO—(C₁-C₄)alkyl group, benzyl,        tetrahydropyranyl, tetrahydropyranylmethyl,        dimethyltetrahydropyranyl, tetrahydrofuryl or        tetrahydrofurylmethyl group;    -   or R₅ and R₆, together with the nitrogen atom to which they are        attached, constitute a heterocyclic radical chosen from:        aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,        perhydroazepinyl, morpholinyl, piperazinyl, tropanyl,        quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl,        2-azabicyclo[2,2,2]octanyl, the said heterocyclic radicals being        unsubstituted or substituted with a phenyl, halophenyl,        trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy,        hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino        group, a group —NR₄R₇, tetrahydropyran-4-ylamino, —CON(R₄)₂,        —CONR₄R′₄, —CH₂CON(R₄)₂, (C₁-C₄)alkyl-CONR₄—,        (C₃-C₈)cycloalkyl-CONR₄—, (C₁-C₄) alkyl-OCONR₄—, (C₃-C₈)        cycloalkyl-OCONR₄—, ((C₁-C₄)alkyl-OCO)₂N— or (C₁-C₄)alkyl-COO—;        or substituted with one or more methyl groups;    -   R′₄ represents a group (CH₂)_(s) linked to the carbon atom        bearing —CONR₄R′₄;    -   R₇ represents a hydrogen atom, a (C₁-C₄)alkyl or an —SO₂CH₃        group or R₄ and R₇, together with the nitrogen atom to which        they are attached, constitute a pyrrolidinyl or piperidinyl        radical;    -   p represents 1, 2, 3, 4 or 5;    -   q represents 0, 1 or 2;    -   r represents 1 or 2;    -   s represents 2 or 3;    -   p+q being less than or equal to 5;    -   p+r being less than or equal to 5;    -   alk represents an alkylene;        with the condition that R₁ and R₂ are not simultaneously a        hydrogen atom.

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may thus exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers, and also themixtures thereof, including racemic mixtures, form part of theinvention. Similarly, the axial and equatorial, endo and exostereoisomers and also mixtures thereof form part of the invention.

The compounds of formula (I) may exist in the form of bases or ofacid-addition salts. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids that are useful, for example, forpurifying or isolating the compounds of formula (I) also form part ofthe invention.

The compounds of formula (I) may also exist in the form of hydrates orsolvates, i.e. in the form of associations or combinations with one ormore molecules of water or with a solvent. Such hydrates and solvatesalso form part of the invention.

In the context of the present invention, the following terms have themeanings given below:

-   -   a halogen atom: a fluorine, a chlorine, a bromine or an iodine;    -   an alkyl group: a linear or branched monovalent saturated        aliphatic group containing 1 to 4 carbon atoms or, where        appropriate, 1 to 8 carbon atoms. Examples that may be mentioned        include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,        tert-butyl, pentyl, neopentyl, tert-pentyl, etc. groups;    -   a cycloalkyl group: a cyclic alkyl group containing 3 to 8        carbon atoms or, where appropriate, 3 to 10 carbon atoms, which        is optionally bridged. Examples that may be mentioned include        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,        cyclooctyl and adamantyl groups;    -   an alkoxy group: a radical —O-alkyl in which the alkyl group is        as defined above;    -   an alkylene group: a linear or branched divalent saturated        aliphatic group containing 1 to 3 carbon atoms or, where        appropriate, 2 to 3 or 2 to 4 carbon atoms.

Among the compounds of formula (I) that are subjects of the invention,mention may be made of a first sub-group of compounds corresponding tothe general formula (I′):

in which:

-   -   R₁ represents a hydrogen or halogen atom or a (C₁-C₄)alkyl,        trifluoroethyl, hydroxyl, (C₁-C₄) alkoxy, trifluoromethoxy,        trifluoroethoxy, (C₃-C₈)cycloalkyloxy, allyloxy,        cyclopropylmethoxy or (C₁-C₄)alkylthio group;    -   R₂ represents a hydrogen or halogen atom or a (C₁-C₈)alkyl,        trifluoroethyl, perfluoro(C₁-C₄)alkyl, (C₃-C₁₀)cycloalkyl,        phenyl, (C₁-C₈)alkoxy, trifluoromethoxy, trifluoroethoxy,        allyloxy, (C₃-C₈)cycloalkylmethoxy, (C₃-C₈)cycloalkyloxy or        (C₃-C₈) cycloalkylmethyl group;    -   R₃ represents a group chosen from:    -   a) a1) —O— (C₂-C₄) alk-A;        -   a2) —O— (C₁-C₄) alk-B;        -   a3) —O-E;    -   b) —(C₁-C₄)alk-A;    -   c) —B;    -   d) d1) —(C₁-C₄)alk-NR₄—(C₂-C₃)alk-A;        -   d2) —(C₁-C₄)alk-NR₄—(C₁-C₃)alk-B;    -   e) e1) —CONR₄—(C₂-C₄)alk-A;        -   e2) —CONR₄—(C₁-C₄)alk-B;        -   e3) —CONR₄-E;    -   f) f1) —CO-D-(C₁-C₂)alk-A;        -   f2) —CO-G-A;

-   -   R₄ represents a hydrogen atom or a (C₁-C₄)alkyl group;    -   A represents a group NR₅R₆;    -   B represents a group

-   -   D represents a group

-   -   E represents a group

-   -   G represents a group

-   -   R₅ and R₆ each represent, independently of each other, a        hydrogen atom or a (C₁-C₆)alkyl, allyl,        (C₂-C₄)alk-O—(C₁-C₄)alkyl, (C₂-C₄)alk-OH, (C₁-C₃)alk-CON(R₄)₂,        (C₂-C₃)alk-NHCO—(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl,        (C₃-C₇)cycloalkylmethyl, benzyl, tetrahydropyranyl,        tetrahydropyranylmethyl, dimethyltetrahydropyranyl,        tetrahydrofuryl or tetrahydrofurylmethyl group;    -   or R₅ and R₆, together with the nitrogen atom to which they are        attached, constitute a heterocyclic radical chosen from:        aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,        perhydroazepinyl, morpholinyl, piperazinyl, tropanyl,        quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl,        2-azabicyclo[2,2,2]octanyl, the said heterocyclic radicals being        unsubstituted or substituted with a phenyl, halophenyl,        trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy,        hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino        group, a group —NR₄R₇, tetrahydropyran-4-ylamino, —CON(R₄)₂,        —CONR₄R′₄, —CH₂CON(R₄)₂, (C₁-C₄)alkyl-CONR₄—,        (C₁-C₄)alkyl-OCONR₄— or (C₁-C₄)alkyl-COO—; or substituted with        one or more methyl groups;    -   R′₄ represents a group (CH₂), linked to the carbon atom bearing        —CONR₄R′₄;    -   R₇ represents a hydrogen atom or a (C₁-C₄)alkyl, or R₄ and R₇,        together with the nitrogen atom to which they are attached,        constitute a pyrrolidinyl or piperidinyl radical;    -   p represents 1, 2, 3, 4 or 5;    -   q represents 0, 1 or 2;    -   r represents 1 or 2;    -   s represents 2 or 3;    -   p+q being less than or equal to 5;    -   p+r being less than or equal to 5;    -   alk represents an alkylene;        with the condition that R₁ and R₂ are not simultaneously a        hydrogen atom.

Among the compounds of formula (I) that are subjects of the invention,mention may be made of a second sub-group of compounds, which aredefined as follows:

R₁ is in position −2 of the phenyl and/or R₂ is in position −5 and/or R₃is in position −4 of the other phenyl; thus more particularly, mentionmay be made of the compounds of formula:

in which R₁, R₂ and R₃ are as defined for (I).

Among these compounds, another sub-group of compounds of formula (Ia)are those in which:

-   -   R₁ represents a halogen atom or a (C₁-C₄)alkyl, hydroxyl,        (C₁-C₄) alkoxy, (C₃-C₈) cycloalkyloxy, allyloxy,        cyclopropylmethoxy or (C₁-C₄)alkylthio group; and/or    -   R₂ represents a halogen atom or a (C₁-C₈)alkyl, trifluoromethyl,        (C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₈)alkoxy, allyloxy,        (C₃-C₈)cycloalkylmethoxy, (C₃-C₈)cycloalkyloxy or (C₃-C₈)        cycloalkylmethyl group; and/or    -   R₃ represents a group chosen from groups a), b), c), d), e)        and f) as defined above for (I).

More particularly, among these compounds, mention may be made of thecompounds in which:

-   -   R₁ represents a (C₁-C₄)alkoxy, cyclopropylmethoxy or        (C₁-C₄)alkylthio group; and/or    -   R₂ represents a halogen atom or a (C₁-C₈)alkyl, trifluoromethyl,        (C₃-C₁₀)cycloalkyl or (C₁-C₈)alkoxy group; and/or    -   —R₃ represents a group f2 or e2.

Among the compounds of formula (I) of the invention, mention may be madeespecially of the following compounds:

-   4-((4-[3-(R)-(acetylamino)pyrrolidin-1-yl]piperidin-1-yl)carbonyl)-N-[4-(5-butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]benzamide;-   ethyl    (1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)piperidin-4-yl)carbamate;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(tetrahydropyran-4-ylamino)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(2-(tetrahydropyran-4-ylamino)ethoxy)benzamide;-   N-(4-(5-ethyl-2-methoxyphenyl)thiazol-2-yl)-4-(3-(tetrahydropyran-4-ylamino)propyl)benzamide;-   N-(4-(5-cyclohexyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-N′-pyrrolidin-2-ylmethylterephthalamide;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-(cyclopropanecarbonylamino)pyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-isobutyrylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-hydroxypyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-N′-((S)-(1-ethylpyrrolidin-2-yl)methyl)terephthalamide;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-hydroxyazetidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(S)-acetylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-N′-piperidin-3-ylterephthalamide;-   N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-hydroxypyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-N′-((S)-(1-ethylpyrrolidin-2-yl)methyl)terephthalamide;-   N-(4-(5-cyclohexyl-2-ethoxyphenyl)thiazol-2-yl)-N′-((S)-(1-ethylpyrrolidin-2-yl)methyl)terephthalamide;-   N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-N′-((S)-(1-ethylpyrrolidin-2-yl)methyl)terephthalamide;-   N-(4-(5-cyclopentyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(tetrahydropyran-4-ylamino)piperidine-1-carbonyl)benzamide;-   N-(4-(5-hexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(tetrahydropyran-4-ylamino)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-formylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(S)-hydroxymethylpyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-propyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclopentyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   ethyl    1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)benzoyl)piperidin-4-yl)pyrrolidin-3-(R)-ylpropionate;-   N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-propionylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-butyrylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclohexyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-acetylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-ethyl-2-ethoxyphenyl)thiazol-2-yl)-N′-((R)-(1-ethylpyrrolidin-2-yl)methyl)terephthalamide;-   methyl    1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)piperidin-4-yl)pyrrolidin-3-yl)carbamate;-   N-(4-(5-cyclopentyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-propionylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-butyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-propionylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   N-(4-(5-cyclopentyl-2-ethoxyphenyl)thiazol-2-yl)-4-(4-(3-(R)-propionylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide;-   ethyl    1-(1-(4-(4-(5-cyclopentyl-2-ethoxyphenyl)thiazol-2-ylcarbamoyl)piperidin-4-yl)pyrrolidin-3-yl)carbamate.

Some of the compounds of formula (I) may also serve as intermediates forthe preparation of other compounds of formula (I), as will be seen inthe examples given later.

In the text hereinbelow, the term “protecting group Pg” means a groupthat firstly allows a reactive function such as a hydroxyl or an amineto be protected during a synthesis, and secondly allows the intactreactive function to be regenerated at the end of the synthesis.Examples of protecting groups and of protection and deprotection methodsare given in “Protective Groups in Organic Synthesis”, Green et al.,2^(nd) Edition (John Wiley & Sons, Inc., New York).

In the text hereinbelow, the term “leaving group” means a group that canbe readily cleaved from a molecule by breaking a heterolytic bond, withloss of an electron pair. This group may thus be readily replaced withanother group during a substitution reaction, for example. Such leavinggroups are, for example, halogens or an activated hydroxyl group such asa mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups andreferences for preparing them are given in “Advanced Organic Chemistry”,J. March, 3^(rd) Edition, Wiley Interscience, pp. 310-316.

In accordance with the invention, the compounds of general formula (I)may be prepared by the process that follows.

This process is characterized in that:

a functional derivative of an acid of formula:

in which R′₃ represents R₃ as defined above for (I) or a precursor ofR₃, is treated with a 2-aminothiazole derivative of formula:

in which R′₁ and R′₂ represent, respectively, R₁ and R₂ or precursors ofR₁ and R₂ as defined for (I);and then, where appropriate, the compound thus obtained of formula:

in which R′₁, R′₂ and R′₃ are, respectively, R₁, R₂ or R₃, or precursorsof R₁, R₂ and R₃, is converted into a compound of formula (I).

The expression “precursor of R₁, R₂ or R₃” means a substituent that maybe converted into R₁, R₂ or R₃ via one or more chemical reactions.

The expression “functional derivative of an acid of formula (II)” meansan acid chloride, a mixed or symmetrical anhydride, or the acid suitablyactivated, for example, withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), for example.

The first step is performed in an aprotic solvent such asdichloromethane, acetonitrile, THF or DMF, in basic medium.

The compounds of formula (II) are prepared via known methods that varydepending on the value of the substituent R₃ or R′₃ of the compound offormula (II).

In the schemes that follow, it is considered that the groups R′₁ and R′₂which represent R₁ and R₂ or a precursor of R₁ and R₂, respectively, maybe converted in a subsequent step using reactions known to those skilledin the art.

When one or more substituents R′₁, R′₂ and/or R′₃ represent a groupcontaining an amine or hydroxyl function, these functions may beintermediately protected: an amine function may be protected with analkanoyl, benzyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl or9-fluorenylmethoxycarbonyl (Fmoc) group, for example; a hydroxylfunction may be protected in ether or ester form, for example.

To prepare a compound of formula (I) in which R₃ represents a group a)as defined above for (I), a compound of formula (II) may be prepared inwhich R₃ represents a group a) by performing the reaction Scheme below,illustrated for a1), followed by using the process according to theinvention.

Y=leaving groupR═(C₁-C₄)alkyl.

The process may also be performed according to Scheme 1, but replacingin the compound of formula (V) the leaving group Y with a hydroxylgroup, according to the Mitsunobu reaction, Bull. Chem. Soc. Japan,1967, 40, 2380.

Alternatively, to prepare a compound of formula (I) in which R₃represents a group a), a compound of formula (IV) containing a group R′₃that is a precursor of R₃ may be prepared, and may then be converted ina subsequent step into the group R₃ according to the following reactionScheme:

Y: leaving group.

Pg: protecting group for oxygen, such as tert-butyl, benzoyl orarylsulphonyl, for example.

By replacing the compound of formula (V) with a compound of formula Y-Ein which E is as described above, the substituent R₅ being optionallyreplaced with a protecting group for nitrogen, a compound of formula (I)in which R₃=a3) is obtained.

A compound of formula (I) in which R₃ represents a) may also be preparedstarting with a compound comprising a group R′₃, which is a precursor ofR₃, according to the reaction Scheme below:

In the final step, the addition of the amine is performed according toSynth. Commun., 1998, 28 (10), 1897-1905, J. Org. Chem., 1992, 57 (11),3218-3225, J. Org. Chem., 1996, 61, 3849-3862, Tetrahedron Lett., 1990,31, 5595-5598.

Another way of preparing a compound of formula (I) in which R₃represents a group a), from a compound of formula (IV) containing R′₃,which is a precursor of R₃, is shown in the reaction Scheme below:

R′=methyl or tolyl

THP=tetrahydropyran-2-yl.

The conversion of the compound of formula (XVIII) by oxidation may beperformed via a Swern oxidation, for example.

An example of the preparation of a compound of formula (II) in whichR′₃=a1) is described below:

Starting with compound (XX) thus obtained, various compounds (II) maythen be prepared by suitably substituting the primary amine.

To prepare a compound of formula (I) in which R₃ is a group a2) or a3),the process may also be performed via the action of a compound offormula (II) in which R₃=a2) or a3) on a compound of formula (III); thecompound of formula (II) being prepared according to the followingreaction Scheme illustrated for a2):

The acids of formula:

allow the preparation of compounds of formula (IV) in which R′₃=c), viaaction on an aminothiazole of formula (III).

To prepare a compound of formula (I) in which R₃ is a group b), theprocess may be performed via the action of a compound of formula (II) inwhich R₃=b) on a compound of formula (III); the compound of formula (II)or the ester thereof being prepared according to the following reactionScheme:

A compound of formula (I) in which R₃ is a group b) may also be preparedby performing the process according to the following reaction Scheme,which repeats the steps of Scheme 3, while adapting them to the presentcase:

In the particular case in which a compound of formula (I) is prepared inwhich R₃ represents a group b), with (C₁-C₄)alk=(CH₂)₃, a compound offormula (IV) in which R′₃ is a precursor of b) may be converted into acompound of formula (I) according to the following reaction Scheme:

The compound of formula (XXVII) may also be obtained via the action ofiodobenzoic acid on a compound of formula (III), followed by the actionof 2-propen-1-ol on the compound thus obtained of formula (XXVIIa):

A compound of formula (I) in which R₃ is b) may also be preparedaccording to the following reaction Scheme:

Hal: halogen atom, preferably chlorine.

Similarly, a compound of formula (I) in which R₃=b) may also be preparedfrom a compound of formula (II) prepared according to the followingScheme:

The compounds of formula (II) in which R₃=c) may be prepared accordingto Syn. Lett., 1998, 4, 379-380.

The processes for preparing the compounds of formula (I) in which R₃ isa group d) are performed in a manner similar to those described for thepreparation of the compounds (I) in which R₃=b).

To prepare a compound of formula (I) in which R₃ is a substituted amidegroup (groups e) and f)), the process may be performed according toeither of Schemes 11 and 12 below, which illustrate the case in whichR₃=e1):

According to this procedure, by using a compound of formula (XXXIIIa) asstarting material, which is reacted with a diamine of formulaNHR₄—(C₂-C₄)alk-A, a compound of formula (I) with R₃=e1) is obtaineddirectly.

In the particular case in which R₃ is a group f2) and G represents apiperidine group, the process may be performed according to thefollowing Scheme:

The compounds thus obtained may then be converted into compounds inwhich NR₅R₆ is as defined in the general formula (I) by deprotection andfunctionalization of the amine NR′₅R′₆, according to the methods knownto those skilled in the art.

The compounds of formula (XXXVIII) may also be prepared from thecompounds of formula (XXXIIIa) according to the following scheme:

To prepare a compound of formula (I) in which R₃ is a group f2) and Grepresents a piperidinyl radical, the process may also be performedaccording to the following Scheme:

Starting with the compound (XXXXI) thus obtained, various compounds offormula (I) in which R₃=f2) may then be prepared by suitablysubstituting the primary amine function.

For example, via the action of tetrahydropyran-4-one, a compound offormula (I) is prepared in which R₃ is a group:

To prepare a compound of formula (I) in which R₃=e) or f), the processmay be performed according to the scheme below which illustrates thecase where R₃=f2) and G represents a piperidine:

or, by inverting the first steps, the process is performed according tothe following scheme:

or, according to another alternative:

Ph=phenylTHP=tetrahydropyran-4-yl.

In the processes represented in Schemes 14, 15 and 16, a protectinggroup for nitrogen that may be used is Boc, as shown, or any othersuitable protecting group Gp, for example an alkanoyl group such asformyl or acetyl, a benzyl group, a 9-fluorenylmethoxycarbonyl (Fmoc)group or a benzyloxycarbonyl or tert-butoxycarbonyl (Boc) group.

The aminothiazoles of formula (III) are prepared by known methods suchas those described in documents EP 518 731, EP 611 766 and WO 99/15525.

In general, thiourea is reacted with a halo ketone of formula 4according to the following reaction scheme:

The substituents R′₁ and R′₂ have the values indicated above, i.e. R′₁and R′₂ represent R₁ and R₂, respectively, as defined for (I) orprecursor groups of R₁ and R₂; Hal represents a halogen atom, preferablybromine, chlorine or iodine.

The halo ketones of formula 4 may be prepared via processes known tothose skilled in the art. For example, the bromo ketones may be obtainedby the action of bromine, cupric bromide or phenyltrimethylammoniumtribromide (PTT) on an acetophenone derivative of formula:

in which R′₁ and R′₂ have the values indicated above, in an organicsolvent such as ethyl acetate, a chlorinated solvent or a mixturethereof, or alternatively an alcohol.

When the acetophenone derivative of formula 5 is not commerciallyavailable, it may be prepared via various methods:

-   -   a Friedel-Crafts reaction on the benzene substituted with R′₁        and R′₂, which is reacted with acetyl chloride or acetic        anhydride, in the presence of a Lewis acid, for instance AlCl₃        or TiCl₄;

the action of acetyl chloride in the presence of palladium on thebenzene substituted with R′₁ and R′₂ after deprotonation of the benzene,for example via the action of butyllithium, followed by addition of zincchloride or manganese iodide. This procedure may be used to prepare anacetophenone derivative of formula 5 in which R′₂=R₂═(C₁-C₄)perfluoroalkyl;

-   -   Fries rearrangement: starting with an acetoxybenzene derivative        of formula:

via the action of a Lewis acid, a hydroxyacetophenone derivative isobtained, of formula:

The hydroxyl function corresponds to a group R₁₁ that may be convertedin a subsequent step into a group —O-Z such as (C₁-C₈)alkoxy,trifluoromethoxy, trifluoroethoxy, allyloxy, (C₃-C₈) cycloalkylmethoxyor (C₃-C₈) cycloalkyloxy.

The conversion of R′₁ into R₁ may be performed either on theaminothiazole of formula (III) or on a compound of formula (I).

The benzene derivatives substituted with R′₁ and R′₂ are commerciallyavailable or may be prepared via methods known to those skilled in theart.

For example, to prepare a compound in which R₁ is a group —O-Z asdefined above, the process is performed in the following manner:

A halobenzene derivative may also be substituted according to the schemebelow:

In the particular case in which R₂ represents a (C₁-C₄)perfluoroalkyl,the process may also be performed according to the reaction schemebelow:

Acids of formula (II) in which R′₃ represents R₃, which is an ethergroup as defined for (I) by a), are described especially in Arch.Pharm., 1962, 295, 292-304; Eur. J. Med. Chem., 1994, 26 (9), 675-686;J. Med. Chem., 2002, 45 (16), 3406-3417; and in documents: WO-02/53534;WO-01/00206; WO-96/21656; WO-00/39087; EP-A-62504; EP-A-393 607;EP-A-997 465.

The acids of formula (II) in which R′₃ represents R₃ which is a group b)or c) as defined for (I) are generally novel. The4-((1-methylpiperidin-4-yl)methylbenzoic and4-((1-ethylpiperidin-4-yl)methylbenzoic acid esters are described inPesticide Sciences, 1995, 44 (1), 96-102.

Thus, a subject of the present invention is also compounds of formula:

in which R′₃ represents R₃ chosen from:a group b): (C₁-C₄) alk-A

or c): B

in which the groups A and B are as defined for (I), on condition thatwhen (C₁-C₄)alk represents a methylene, B is other than piperidinyl; orR′₃ represents a precursor of R₃, especially a group in which the amineand/or hydroxyl functions that may be present are protected.

The esters, especially the (C₁-C₄) aliphatic esters or benzyl esterswhich are unsubstituted or substituted on the phenyl with a methoxygroup, of the acids of formula (IIb) are also novel and form part of theinvention.

The acids of formula (II) in which R′₃ represents R₃ which is a group e)or f) as defined for (I) are generally novel. Compounds of formula (II)in which R₃ represents a group e1) are described in documentsWO-98/56760 and U.S. Pat. No. 5,411,984.

Thus, a subject of the present invention is also compounds of formula:

in which R′₃ represents R₃ chosen from a group e2), e3), f1), f2), f3),f4), f5) and f6) as defined for (I); or R′₃ represents a group that is aprecursor of R₃, especially a group in which the amine and/or hydroxylfunctions that may be present are protected.

The esters, especially the (C₁-C₄) aliphatic esters or benzyl esterswhich are unsubstituted or substituted on the phenyl with a methoxygroup, of the acids of formula (IIe) are also novel and form part of theinvention.

In particular, the acids of formula:

in which G′p represents hydrogen or a protecting group for nitrogen suchas: Boc, Fmoc, benzyloxycarbonyl, benzyl or (C₁-C₄) alkanoyl,and also the (C₁-C₄)alkyl esters thereof of formula (XXXXIV) or thebenzyl esters thereof which are unsubstituted or substituted on thephenyl with a methoxy group, are novel and constitute a specific subjectof the present invention.

The intermediate compounds of formulae (XXXXVI), (XXXXVII) and(XXXXVIII) that are useful for preparing compounds of formula (XXXXV)are also novel.

Thus, a subject of the present invention is also a compound of formula:

in which the amine functions are free or protected with a protectinggroup, for instance an Fmoc, benzyl, tert-butoxycarbonyl,benzyloxycarbonyl or (C₁-C₄)alkanoyl group.

The 2-aminothiazoles of formula (III) are generally known, especiallyfrom the following documents: EP-A-819 681, EP-A-44442 or Indian J.Chem., section B, 1987, 26B (3), 287-289.

The intermediate compounds of formula (IV), i.e. the compounds offormulae X, XIII, XIV, XVII, XVIII, XIX, XXVI, XXVII, XXVIIa, XXIX,XXXIII, XXXIIIa, XXXIV, XXXIVa, XXXVIII, XXXX and XXXXIX are novel andconstitute a further subject of the present invention.

Moreover, the intermediate compounds of formula (IV) in which the groupR′₃ comprises a protected amine function, i.e. a group —NGp in place ofa group —NR₅, are also novel.

A subject of the invention is also the compounds of formula:

in which:

-   -   R′₁ and R′₂ represent, respectively, R₁ or R₂ or precursors of        R₁ and R₂ as defined for the compounds of formula (I); more        particularly, R′₁ and R′₂ represent, respectively, R₁ and R₂;    -   R′₃ represents a group chosen from:        -   —OPg, Pg being a protecting group such as tert-butyl,            benzoyl or arylsulphonyl (phenylsulphonyl, tolylsulphonyl or            naphthylsulphonyl);        -   —O—(C₁-C₃)alk-Q, Q being a dimethoxymethyl, diethoxymethyl            or formyl group;        -   —O—(C₂-C₄)alk-OX, X representing a hydrogen atom, a            tetrahydropyranyl group or a group SO₂R′, R′ being a methyl            or tolyl group;        -   —(C₁-C₃)alk-Q;        -   —(C₁-C₄)alk-Hal, Hal representing a halogen atom;        -   —I;        -   —COOH; —COOR with R representing a hydrogen atom, a            (C₁-C₄)alkyl or a benzyl which is unsubstituted or            substituted on the phenyl with a methoxy group;        -   —CONH—(C₁-C₃)alk-Q;

-   -   -   Gp representing a protecting group for nitrogen, such as            Fmoc, (C₁-C₄)alkanoyl, benzyl, benzyloxycarbonyl or            tert-butoxycarbonyl;

-   -   -   -   a) a1) —O—(C₂-C₄)alk-A′;                -   a2) —O— (C₁-C₄)alk-B′;                -   a3) —O-E′;            -   b) —(C₁-C₄)alk-A′;            -   c) —B′;            -   d) d1) —(C₁-C₄)alk-NR₄—(C₂-C₃) alk-A′;                -   d2) —(C₁-C₄) alk-NR₄—(C₁-C₃)alk-B′;            -   e) e1) —CONR₄—(C₂-C₄)alk-A′;                -   e2) —CONR₄—(C₁-C₄)alk-B′;                -   e3) —CONR₄-E′;            -   f) f1) —CO-D-(C₁-C₂)alk-A′;                -   f2) —CO-G-A′;

in which:

-   -   A′, B′ and E′ represent, respectively, the groups A, B and E as        defined for (I) in which R₅ is replaced with Gp;    -   Gp represents a protecting group for nitrogen such as:    -   Boc, Fmoc, (C₁-C₄)alkanoyl, benzyloxycarbonyl or benzyl.

More particularly, the present invention relates to the compounds offormula (IV) in which:

-   -   R′₁ is in position −2 of the phenyl and is such as R₁, defined        for (I);    -   R′₂ is in position −5 of the phenyl and is such as R₂ defined        for (I);    -   R′₃ is in position −4 of the other phenyl group and is as        defined above.

The preparations and examples that follow illustrate the preparation ofcertain compounds in accordance with the invention. These examples arenot limiting and merely illustrate the present invention. The numbers ofthe compounds illustrated refer to those given in the tables later. Inthe description, the following abbreviations are used:

RT: room temperature

dec.: decomposition

DCM: dichloromethane

DMF: dimethylformamide

Et₃N: triethylamine

BOP: benzotriazol-1-yl-oxytris(dimethyl-amino)phosphoniumhexafluorophosphate

Boc: tert-butyloxycarbonyl

ether: ethyl ether

MTBE: methyl tert-butyl ether

Me: methyl

Et: ethyl

Pr: propyl

Bu: butyl

Pn: pentyl

Hex: hexyl

DIPEA: diisopropylethylamine

THP: tetrahydropyran-4-yl.

The compounds are characterized by:

The proton magnetic resonance (¹H NMR) spectra are recorded at 200 MHzin DMSO-d₆, using the DMSO-d₆ peak as reference. The chemicaldisplacements δ are expressed in parts per million (ppm). The signalsobserved are expressed as follows: s: singlet; bs: broad singlet; d:doublet; dd: doubled doublet; t: triplet; dt: doubled triplet; q:quartet; m: unresolved peak; mt: multiplet.

For all the compounds synthesized in the Preparations and Examples thatfollow, it is checked that the NMR spectra recorded are in accordancewith the expected structure.

The compounds according to the invention are analyzed by LC/UV/MS(liquid chromatography/UV detection/mass spectrometry) coupling. Themolecular peak (MH⁺) and the retention time (t) are measured.

A machine sold by Waters and a column of 2.1×50 mm are used, with 3.5 μmparticles, at room temperature, with a flow rate of 0.4 ml/minute.

The eluent is made up as follows:

solvent A: 0.005% trifluoroacetic acid (TFA) in water

solvent B: 0.005% TFA in acetonitrile.

Time (minutes) % B Gradient 0 0 10 90 15 90 15.5 0 20 0

The UV detection is performed at 210±8 nm and the mass detection isperformed after electronic ionization (electrospray ionization or ESI)in positive mode.

Preparation of the Intermediates of Formula (III) Preparation 1.14-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-amine A)1-(2-Hydroxy-5-propoxyphenyl)ethanone

10 g of 2,5-dihydroxyacetophenone suspended in 100 ml of acetone areplaced in a 500 ml round-bottomed flask and 9.14 g of anhydrous K₂CO₃are added, followed by addition of 12.4 g of propyl iodide. The reactionmedium is refluxed for 30 hours. After cooling to room temperature, themedium is filtered through Celite® and then concentrated. The brown oilobtained is taken up in EtOAc, filtered, washed with water, with 2M HClsolution and then with saturated NaCl solution. The organic phase isevaporated to give a black paste. The paste is taken up in chloroformand filtered. The medium is concentrated to give 11.4 g of a blacksolid. This solid is taken up in absolute ethanol. The solution isplaced in a freezer for 10 minutes; a solid precipitates out, and iscollected by filtration. The filtrate is concentrated, taken up inethanol, cooled in a freezer and then filtered again. This operation isrepeated four more times to give 8.35 g of the expected compound in theform of a powder.

B) 1-(2-Methoxy-5-propoxyphenyl)ethanone

49.8 g of K₂CO₃ are added to a solution of 35 g of the above solid in350 ml of DMF, followed by addition of 22.4 ml of methyl iodide. Thereaction medium is heated for 12 hours at 60° C. After cooling to roomtemperature, the medium is filtered through Celite®, diluted with etherand washed with 2M HCl solution. The aqueous phase is extracted twicewith ether. The combined organic phases are washed with dilute sodiumhydroxide solution and then washed twice with water and with saturatedNaCl solution. The organic phase is dried over MgSO₄ and then evaporatedto give 35.55 g of a brown oil. The oil is distilled under reducedpressure at 115° C. to give 32.8 g of the expected compound in the formof an oil.

C) 2-Bromo-1-(2-methoxy-5-propoxyphenyl)ethanone

4.8 ml of bromine are added dropwise to a solution of 16.4 g of the oilobtained in the preceding step in 100 ml of methanol. The medium isstirred for 30 minutes at room temperature and then evaporated. The oilobtained is taken up in dichloromethane, washed three times with waterand then dried over MgSO₄ and then evaporated to give 24.5 g of a brownoil.

D) 4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-amine

24.5 g of thiourea are added to a solution of 42 g of the bromo ketoneprepared in the preceding step in 200 ml of ethanol. The medium isrefluxed for 1 hour 30 minutes. The medium is then placed in arefrigerator for 12 hours, and then filtered. The solid thus collectedis rinsed with a small amount of cold ethanol and then with ether. 25 gof hydrobromide are recovered.

The solid is suspended in a water/dichloromethane mixture and the baseis restored by adding sodium hydroxide. The aqueous phase is extractedtwice with dichloromethane. The combined organic phases are dried overMgSO₄ and then evaporated. The oil obtained is chromatographed on silicagel to give 12 g of the expected product in the form of powder. m.p.=76°C.

Preparation 1.2 4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-amine A)4-Butylphenyl acetate

A solution of 10 g of 4-n-butylphenol, 10 ml of Ac₂O and 8 ml ofpyridine is stirred at reflux in 10 ml of dichloromethane. After 2hours, the medium is cooled to room temperature, diluted withdichloromethane, washed with water, washed with 1M HCl solution, washedwith saturated CuSO₄ solution, washed with water and dried over MgSO₄.After evaporation, 10.8 g of the expected compound are recovered in theform of an oil.

B) 1-(5-Butyl-2-hydroxyphenyl)ethanone

3.22 g of AlCl₃ are added portionwise to 5 g of the preceding oil in a100 ml round-bottomed flask. The medium is heated at 130° C. for onehour. After cooling to room temperature, a solution of ice-cold wateracidified with 35% HCl is poured onto the crude reaction product. Themedium is placed in an ultrasonication bath. EtOAc is added to obtain,after 15 minutes, dissolution of the medium. The aqueous phase isextracted 3 times with EtOAc and the organic phases are washed withwater and then with saturated NaCl solution. After drying over MgSO₄ andevaporation, 4.5 g of a yellow oil are obtained.

C) 1-(5-Butyl-2-methoxyphenyl)ethanone

1.44 g of K₂CO₃ and then 0.648 ml of methyl iodide are added to asolution of 1 g of the preceding oil in 10 ml of DMF. The medium isheated at 60° C. overnight. After cooling to room temperature, themedium is filtered through Celite®, diluted with ether and washed with2M HCl solution. The aqueous phase is extracted twice with ether. Thecombined organic phases are washed with dilute sodium hydroxide solutionand then washed twice with water and with saturated NaCl solution. Theorganic phase is dried over MgSO₄ and then evaporated to give 1.27 g ofa brown oil. The oil is purified by chromatography to give 0.66 g of theexpected compound.

D) 4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-amine

0.19 ml of bromine is added to a solution of 0.66 g of the product fromthe preceding step in 10 ml of methanol. The medium is stirred for 10minutes and then evaporated and taken up in dichloromethane. The organicphase is washed 3 times with water and then dried over MgSO₄. 0.79 g ofthe expected product is recovered after evaporation. This compound isdissolved in 5 ml of ethanol in the presence of 0.46 g of thiourea andthe medium is refluxed for 2 hours 30 minutes. A solid precipitatesduring cooling to room temperature. The solid thus collected is rinsedwith a small amount of cold ethanol and then with ether. 0.6 g of thehydrobromide is thus recovered.

The solid is suspended in a water/dichloromethane mixture and the baseis restored by addition of sodium hydroxide. The aqueous phase isextracted twice with dichloromethane. The combined organic phases aredried over MgSO₄ and then evaporated to give 0.34 g of a yellow oil,which crystallizes slowly. The mother liquors are evaporated and thenstirred in a water/dichloromethane mixture and the base is restored byaddition of sodium hydroxide. The aqueous phase is extracted twice withdichloromethane. The combined organic phases are dried over MgSO₄ andthen evaporated. The oil obtained is chromatographed on silica gel togive 0.18 g of the expected compound; m.p.=48° C.

Preparation 1.34-(5-Cyclohexyl-2-methoxyphenyl)-1,3-thiazol-2-amino-1-cyclohexyl-4-methoxybenzene

A) 7.84 g of K₂CO₃ are added to a solution of 5 g of 4-cyclohexylphenolin 60 ml of DMF, followed by addition of 3.53 ml of methyl iodide. Themedium is heated at 60° C. overnight. After cooling to room temperature,the medium is filtered through Celite® and then diluted with ether andhydrolyzed with water. The aqueous phase is acidified and then extractedwith 3×50 ml of ether. The combined organic phases are washed withdilute sodium hydroxide solution and then washed twice with water andwith saturated NaCl solution. The organic phase is dried over MgSO₄ andthen evaporated to give 4.31 g of the expected compound in the form of asolid. m.p.=67° C.

B) 1-(5-Cyclohexyl-2-methoxyphenyl)ethanone

A suspension of 5.6 g of AlCl₃ in 40 ml of dichloromethane is cooled to−10° C. 3 ml of AcCl and 4 g of the compound from the preceding step areadded. The medium is stirred for one hour at −10° C. and then pouredinto a beaker containing ice mixed with 35% HCl. After separation of thephases by settling, the combined organic phases are dried over MgSO₄ andthen evaporated to give 4.54 g of the expected product.

C) 4-(5-Cyclohexyl-2-methoxyphenyl)-1,3-thiazol-2-amine

1.16 ml of bromine are added dropwise to a solution of 4.5 g of theproduct from the preceding step in 25 ml of methanol. The medium isstirred for 30 minutes at room temperature and then becomes veryviscous. A further 5 ml of methanol are added, followed by addition of3.23 g of thiourea. The medium is refluxed for 2 hours. After cooling toroom temperature, a solid precipitates out. The solid is collected andthen rinsed with a small amount of cold methanol. The solid is suspendedin a water/dichloromethane mixture and the base is restored by additionof sodium hydroxide. The aqueous phase is extracted twice withdichloromethane. The combined organic phases are dried over MgSO₄ andthen evaporated to give 3.33 g of the expected compound in the form of asolid. m.p.=113° C.

Preparation 1.24 4-(5-Pentafluoroethyl-2-methoxyphenyl)thiazol-2-ylamineA) 1-Methoxy-4-pentafluoroethylbenzene

8.3 g of potassium pentafluoropropionate and 9.8 g of CuI are introducedinto a 500 ml three-necked flask equipped with Dean-Stark apparatus anda condenser, under an inert atmosphere. 90 ml of DMF and 110 ml oftoluene are added. The medium is heated to 140° C. under nitrogen and 80ml of toluene are distilled off. The medium is then cooled to RT andthen deoxygenated by sparging with nitrogen. 6 g of iodoanisole are thenadded, followed by heating at 155° C. for 20 hours. After cooling to RT,the medium is diluted with 200 ml of a water/ethyl ether mixture. Themedium is then filtered through Celite®. The organic phase is washed 3times with water, dried over MgSO₄ and then evaporated to give 4.3 g ofa brown oil.

B) 1-(2-Methoxy-5-pentafluoroethylphenyl)ethanone

7.4 ml of BuLi at 2.5M in hexane are added, at −70° C., to a solution of3.5 g of 1-methoxy-4-pentafluoroethylbenzene in 50 ml of anhydrous THF.The medium is stirred for 30 minutes at −70° C. and then for 45 minutesat 0° C. 15.5 ml of a 1M solution of zinc chloride in ether are thenadded. After stirring for 10 minutes at 0° C., 1.33 ml of acetylchloride are added. The medium is then deoxygenated with nitrogen and332 mg of benzyl(chloro)bis(triphenylphosphine)palladium in 5 ml ofanhydrous THF are introduced. The medium is stirred for 2 hours 30minutes at 0° C. and then for 72 hours at RT. The medium is poured onto2.5M HCl solution and then extracted with ether. The organic phase iswashed with 5% NaHCO₃ in water, with water and then with saturated NaClsolution. After drying over MgSO₄ and evaporation, the crude product ispurifed by flash chromatography on silica to give 2.25 g of a whitesolid. m.p.=47° C.

C) 4-(2-Methoxy-5-pentafluoroethylphenyl)thiazol-2-ylamine

0.5 ml of bromine dissolved in 8 ml of methanol is added to a solutionof 2.25 g of the product obtained from the preceding step in 10 ml ofmethanol. The medium is stirred for 10 minutes and then evaporated andtaken up in dichloromethane. The organic phase is washed 3 times withwater and then dried over MgSO₄. 2.63 g of the brominated product arerecovered after evaporation. This compound is dissolved in 15 ml ofmethanol in the presence of 1.25 g of thiourea and the medium isrefluxed for 2 hours. A solid precipitates during cooling to RT. Thesolid thus collected is rinsed with ethyl ether. The solid is suspendedin a water/dichloromethane mixture and the base is restored by additionof sodium hydroxide. The aqueous phase is extracted twice withdichloromethane. The combined organic phases are dried over MgSO₄ andthen evaporated to give 1.63 g of a yellow solid.

m.p.=125° C.

By working according to the above procedures, the compounds of formula(III) described in the table below are prepared.

TABLE 1 (III)

Prepa- Charac- ration teri- No. R₁ R₂ Salt zation 1.1 -OMe -OPr — m.p. =76° C. 1.2 -OMe -nBu — m.p. = 48 ° C. 1.2a -OMe -nBu HBr m.p. = 186° C.1.3 -OMe

— m.p. = 113° C. 1.4 -OMe -nPr — m.p. = 85° C. 1.5 -OEt -Et — m.p. = 83°C. 1.6 -OMe -Et — m.p. = 100° C. 1.7 -OEt

— m.p. = 110° C. 1.8 -OMe

— m.p. = 110° C. 1.9 -OEt -nBu — m.p. = 65° C. 1.10 -OMe CF₃ — m.p. =144° C. 1.11 -OMe -iPr — m.p. = 109° C. 1.12 -OMe Me — m.p. = 121° C.1.13

-nBu — m.p. = 59° C. 1.14 -OMe

— m.p. = 91-93° C. 1.15 -OMe Phenyl — m.p. = 116° C. 1.16 —Cl CF₃ — m.p.= 110° C. 1.17 -OEt Me — m.p. = 124° C. 1.18 —SO₂Et -nBu — m.p. = 121°C. 1.19 -OMe —CH(nPr)₂ HCl MH⁺= 305.4 t = 7.61 1.20 -OnPr -nBu — m.p. =63° C. 1.21 -OMe -nHex — m.p. = 43° C. 1.22 -OMe Adamantyl — m.p. =81-82 ° C. 1.23 -OEt -nHex — m.p. = 75° C. 1.24 -OMe CF₃CF₂ — m.p. =125° C. 1.25 -OEt CF₃CF₂ — MH⁺ = 338 T = 7.88 1.26 -OEt -nPr — m.p. = 87° C. 1.27 -OEt cyclo- — m.p. = pentyl 128° C.

Preparation 2.1 N-(Boc),N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine A)1-Benzyl-N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine (XXXXVI)

19 g of 4-amino-1-benzylpiperidine are placed in 50 ml of1,2-dichloroethane under dry nitrogen and 10 g of tetrahydropyran-4-onein 20 ml of 1,2-dichloroethane are added; after stirring for 10 minutes,29.6 g of NaBH(OAc)₃ are added and the mixture is then stirred for oneday. 10% Na₂CO₃ solution and EtOAc are added to the reaction medium andthe phases are then separated by settling. The organic phase is washedwith 10% Na₂CO₃ solution and then with saturated NaCl solution, and thendried over MgSO₄ and evaporated under vacuum. 23.4 g of the expectedcompound are obtained. m.p.=60° C.

B) 1-Benzyl-N-Boc, —N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine

14.92 g of the compound obtained in the preceding step are placed in 100ml of EtOAc, the solution is then cooled in an icebath and 12.46 g of(Boc)₂O in 30 ml of EtOAc are added. This mixture is heated at 50° C.for 4 days and then stirred for 2 days at room temperature. The reactionmedium is washed with water (3 times), dried over MgSO₄ and thenevaporated. The oil obtained crystallizes, and the solid is trituratedfrom pentane, filtered off and dried at 60° C. over P₂O₅. 15.9 g of theexpected compound are obtained, m.p.=104° C.

C) N-(Boc),N-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine

15.8 g of the compound from the preceding step are placed in 100 ml ofMeOH with 1 g of 10% palladium-on-charcoal, and the mixture ishydrogenated under atmospheric pressure at 30° C. for one day. Themedium is filtered through Celite® and then rinsed with MeOH. Afterevaporating the filtrate, 11.15 g of the expected compound, whichcrystallizes, are obtained. m.p.=125° C.

Preparation of the Intermediates of Formula (II) Preparation 3.14-(2,2-Diethoxyethoxy)benzoic acid

(II): R₃′=4—OCH₂CH(OEt)₂

A) Methyl 4-(2,2-diethoxyethoxy)benzoate

A mixture containing 10 g of methyl 4-hydroxybenzoate and 22.71 g ofK₂CO₃ in 100 ml of THF is heated at 100° C. for 5 min and cooled to roomtemperature, 15.54 g of 2-bromo-1,1-diethoxyethane are added and themixture is stirred for 2 hours at room temperature and then for 32 hoursat 100° C., and is allowed to return to room temperature. The inorganicmaterial is filtered off and then rinsed with DMF. The filtrate isevaporated and then taken up in DCM, washed with water (3 times) andthen with saturated NaCl solution, dried over MgSO₄ and evaporated.16.68 g of the expected compound (greater than the theoretical mass) areobtained.

B) 4-(2,2-Diethoxyethoxy)benzoic acid

8.08 g of the ester obtained in the preceding step are placed in 50 mlof methanol with 16 ml of 5N NaOH and stirred for 6 hours. Afterevaporation of the solvent, the residue is taken up in water and 1.2MHCl is then added to pH=3; this mixture is filtered and rinsed withwater to obtain a precipitate, which is dried under vacuum. The filtrateis extracted twice with DCM and then dried over MgSO₄. 7.29 g in totalof the expected compound are obtained.

Preparation 3.24-((4-(N-Boc)tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)carbonyl)benzoicacid, triethylamine salt

A) Methyl 4-((4-N-Bocamino)piperidin-1-ylcarbonyl)benzoate

A mixture containing 5.39 g of the monomethyl ester of terephthalicacid, 40 ml of CH₃CN, 6 ml of Et₃N, 14.8 g of BOP and 5 g of4-(N-Bocamino)piperidine is stirred at room temperature for 4 days. Thereaction medium is diluted with EtOAc and then washed 4 times with 10%Na₂CO₃ solution and then 4 times with water. The resulting solution isdried over MgSO₄ and then concentrated to dryness and then taken up inan Et₂O/cyclohexane mixture. The resulting solution is filtered and thendried to give 6.66 g of the expected compound. m.p.=128-130° C.

B) Methyl 4-((4-aminopiperidin-1-yl)carbonyl)benzoate hydrochloride

17.66 g of the compound from the preceding step are placed in 120 ml ofa 4M solution of HCl in dioxane, with stirring at room temperature for 2hours. Ether is added and the stirring is continued for a further onehour. The mixture is filtered, washed with ether and then dried to give15 g of the expected compound. m.p.=236-238° C.

C) Methyl4-((4-(tetrahydro-2H-pyran-4-ylamino)piperidin-1-yl)carbonyl)benzoate

A mixture containing 15 g of the compound from the preceding step in 50ml of DMF, 5 g of tetrahydro-4H-pyran-4-one and 4 ml of Et₃N is stirredovernight. 1.36 ml of AcOH, 12.7 g of NaBH(OAc)₃ and 50 ml of DMF areadded and stirring is continued for 3 hours. The reaction medium isconcentrated to dryness and then taken up in DCM and washed with 10%Na₂CO₃ solution. The phases are separated by settling and the organicphase is then washed with water (3 times), dried over MgSO₄ andconcentrated to dryness. 9.5 g of the expected compound are obtained inthe form of a solid. m.p.=129° C.

D) Methyl4-((4-((N-Boc)tetrahydro-2H-pyran-4-ylamino)piperidin-1-yl)carbonyl)benzoate

A mixture containing 3.16 g of the compound from the preceding step in12 ml of DCM is refluxed for 10 hours in the presence of 4.5 g of Boc₂Oand 1.65 ml of Et₃N. After cooling the reaction medium, it is washedwith a buffer solution at pH=2 (3 times) and then with water (3 times).The organic phase is dried over MgSO₄ and then concentrated to drynessto give 4.63 g of the expected compound.

E)4-((4-(N-Boc)tetrahydro-2H-pyran-4-yl)amino)piperidin-1-yl)carbonyl)benzoicacid, Et₃N salt

4 g of the compound from the preceding step are stirred for 48 hours in100 ml of 5N NaOH in methanol. The MeOH is removed by evaporation, thecrude product is taken up in water and the aqueous phase is washed withDCM and then acidified with HCl to pH=3. The resulting phase is filteredand washed with ether, and the solid obtained is then taken up inDCM/water/Et₃N. The aqueous phase is extracted with DCM and then driedover MgSO₄ and concentrated to dryness to give 700 mg of the expectedcompound in solid form. MH⁺=433.3; t=6.71.

The corresponding free acid is prepared: m.p.=190° C., MH⁺=433.3;t=6.70.

Preparation 3.34-(4-((R)-3-(N-Boc)-pyrrolidin-1-yl)piperidine-1-carbonyl)benzoic acid

A) tert-butyl (1-(benzylpiperidin-4-yl)pyrrolidin-3-yl)carbamate

4.66 g of 1-benzyl-4-piperidone in 6 ml of dichloroethane are added to asolution of 4.6 g of (3R)-(3-tert-butoxycarbonylamino)pyrrolidine in 5ml of dichloroethane. After 20 minutes at RT, 7.31 g of NaBH(OAc)₃ areadded, while keeping the medium at a temperature below 20° C., followedby addition of 20 ml of dichloroethane to dissolve the medium, whichsets to a solid. The medium is stirred at RT for 24 hours, hydrolyzed byaddition of aqueous 10% Na₂CO₃ solution and diluted with ethyl acetate.After separation of the phases by settling, the organic phase is washedwith aqueous 10% Na₂CO₃ solution, then with saturated NaCl solution andthen dried over MgSO₄ and evaporated. The crude product is trituratedfrom ether, filtered, rinsed with ether and then dried to give 7.38 g ofa white solid.

m.p.=118° C.

B) (tert-Butyl 1-piperidin-4-ylpyrrolidin-3-yl)carbamate

A solution of 7.37 g of the compound described above in 50 ml ofmethanol is hydrogenated at atmospheric pressure and at RT in thepresence of 1 g of 10% Pd/C for 12 hours. The medium is filtered throughCelite® and the solid is rinsed with methanol. After evaporating off thefiltrate, 5.2 g of an oil which solidifies after trituration areobtained, and is used without further purification for the followingstep.

C) Methyl4-(4-((R)-3-(N-Boc)pyrrolidin-1-yl)piperidin-1-carbonyl)benzoate

3.8 g of terephthalic acid monomethyl ester are added to a solution of4.75 g of the compound obtained in the preceding step in 35 ml ofacetonitrile, followed by addition of 9.4 g of BOP and then 2.2 g oftriethylamine. The medium is stirred at RT for 24 hours and thenconcentrated. The crude product is taken up in ethyl acetate, washedtwice with water and then twice with aqueous 10% Na₂CO₃ solution, andthen with saturated NaCl solution. After drying the organic phase overMgSO₄ and evaporation, 8.62 g of crude product are recovered and aretriturated from an ether/ethyl acetate mixture. After filtration, 5.28 gof the expected product are collected.

D) 4-(4-((R)-3-(N-Boc)pyrrolidin-1-yl)piperidine-1-carbonyl)benzoic acid

1.17 g of sodium hydroxide are added to a solution of 5.05 g of theester obtained in the preceding step in 20 ml of methanol. The medium isstirred at RT for 12 hours and then evaporated and taken up in water.The aqueous phase is washed with ether and then acidified to pH=5 andextracted twice with ethyl acetate. The organic phase is dried overMgSO₄ and then concentrated. The aqueous phase is evaporated and thendried by azeotropic distillation with ethanol. The residue is taken upin ethanol and filtered through Celite®, and the filtrate is evaporated.The two crude products are combined to give 3.65 g of the expected acid.

MH⁺=418 at t=4.7 minutes

Preparation of the Intermediates of Formula (Iv) Preparation 4.1.1

N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-((4-oxopiperidin-1-yl)carbonyl)benzamide

A suspension containing 0.86 g of the aminothiazole from Preparation1.2, 1 g of 4-((4-oxopiperidin-1-yl)carbonyl)benzoic acid and 0.6 ml ofEt₃N in 8 ml of acetonitrile is stirred at RT for 3 days and 1.9 g ofBOP are added. The precipitate formed is filtered off and then washedwith 0.3 ml of CH₃CN and then with 1 ml of ether, to give 0.85 g of theexpected compound.

m.p.=184° C.

Compound (XXXVIII) may also be prepared according to the followingmethod.

4.7 g of 4-piperidone hydrochloride monohydrate are added to a solutionof 10.4 g of the acid prepared via the method described in 4.2.1 in 50ml of acetonitrile, followed by addition of 15.7 g of BOP. At 0° C.,13.3 ml of DIPEA are added and the temperature is allowed to return toRT. After stirring for 24 hours at RT, the reaction medium is filtered,the solid is rinsed with acetonitrile and the filtrate is thenconcentrated and taken up in dichloromethane. The organic phase iswashed with 10% Na₂CO₃, then with 0.5M HCl and then with saturated NaClsolution. After drying the organic phase over MgSO₄, 11.33 g of theexpected product are recovered.

By working in a similar manner, the compounds described in the tablebelow were prepared.

TABLE 2 (XXXVIII)

Preparation R₁ R₂ Characterization 4.1.1 MeO nBu m.p. = 184° C. 4.1.2MeO nPrO m.p. = 196° C. (compound 242) 4.1.3 MeO Me m.p. = 183° C. 4.1.4MeO Et m.p. = 180° C. 4.1.5 MeO nPr m.p. = 172° C. 4.1.6 MeO Cyclohexylm.p. = 186° C. dec. (compound 243) 4.1.7 EtO Cyclohexyl m.p. = 236° C.(compound 244) 4.1.8 EtO Et m.p. = 160° C. 4.1.9 MeO Cyclopentyl MH⁺ =504.5 t = 10.55  4.1.10 -OEt -nBu MH⁺ = 506 t = 10.3

Preparation 4.2.14-(((4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)amino)carbonyl)benzoicacid

(XXXIIIa): R₁=2-OMe; R₂=5-nBu; R′₃=4-COOH

5 g of aminothiazole from Preparation 1.2, 4.12 g of methyl4-carboxybenzoate and then 1.85 ml of Et₃N, 25 ml of CH₃CN and 10.13 gof BOP are mixed together and stirred for 4 days at room temperature.The precipitate formed is filtered off and then washed withacetonitrile. The precipitate is then taken up in a mixture of EtOAc andsaturated Na₂CO₃ solution. After separation of the phases by settling,the aqueous phase is extracted with DCM. The combined organic phases aredried over MgSO₄ and concentrated. 3.18 g of the expected compound areobtained in the form of a methyl ester. This ester is suspended in 34 mlof MeOH and 5.3 ml of 5N sodium hydroxide are then added. After stirringfor 5 days at room temperature, the reaction medium is concentrated todryness. The solid obtained is dissolved in 5 ml of water and thenwashed twice with 50 ml of EtOAc. The aqueous phase is acidified with 1MHCl to pH=2 and the precipitate formed is filtered off and then washedwith ether. After drying, 2.78 g of the expected compound are obtainedin the form of a gum. m.p.=160° C.

By working as described for the above preparation, the intermediatecompounds described in the table below were prepared.

TABLE 3 (XXXIII) and (XXXIIIa)

Prepara- tion R₁ R₂ R Salt Characterization 4.2.1 MeO- nBu H — MH ⁺ =410 t = 21.53 4.2.2 MeO- nPrO Me — m.p. = 180° C. 4.2.3 MeO- nPrO H HClMH⁺ = 412 t = 6.11 4.2.4 MeO- nBu Me — MH⁺ = 424 t = 21.35 4.2.5 MeO-nPr Me — — 4.2.6 MeO- nPr H — MH⁺ = 396 t = 8.17 4.2.7 EtO- Et H TFA MH⁺= 396 t = 14.45 m.p. = 250° C. 4.2.8 EtO- Et tBu — NMR 4.2.9 MeO-Cyclohexyl Me — MH⁺ = 440 t = 8.11 4.2.10 MeO- Cyclohexyl H — MH⁺ = 436t = 10.49 m.p. > 260° C. 4.2.11 EtO- Cyclohexyl Me — — 4.2.12 EtO-Cyclohexyl H — MH⁺ = 450 t = 11.05 4.2.13 MeO- Et Me — NMR 4.2.14 MeO-Et H — NMR 4.2.15 MeO- nHex Me — MH⁺ = 453 t = 11.9 4.2.16 MeO- nHex H —MH⁺ = 439 t = 11.0 4.2.17 EtO- nBu Me — MH⁺ = 439 t = 12.1 4.2.18 EtO-nBu H — MH⁺ = 425 t = 8.6

NMR: Preparation 4.2.8.: 1.2 ppm:t:3H, 1.6 ppm:t:3H, 1.7 ppm:s:9H, 2.7ppm:m:2H, 4.2 ppm:q:2H, 7.0-7.2 ppm:m:2H, 7.8 ppm:s:1H; 8.0-8.3ppm:m:5H, 12.9 ppm:bs:1H.

NMR: Preparation 4.2.13.: 1.2 ppm:t:3H, 2.6 ppm:q:2H, 3.9 ppm:s:6H,7.0-7.2 ppm:m:2H, 7.7 ppm:s:1H; 8.0-8.4 ppm:m:5H, 12.8 ppm:bs:1H.

NMR: Preparation 4.2.14.: 1.2 ppm:t:3H, 2.7 ppm:q:2H, 3.9 ppm:s:3H,7.0-7.2 ppm:m:2H, 7.7 ppm:s:1H; 8.0-8.4 ppm:m:5H, 12.6-13 ppm:bs:1H;13.2-13.5 ppm:bs:1H.

Preparation 4.3.1N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-(2-chloroethyl)benzamide

(XXIX): R₁=2-OMe; R₂=5-nBu; R′₃=4-(CH₂)₂Cl

A mixture containing 3 g of aminothiazole from Preparation 1.2, 10 ml ofCH₃CN, 2.54 g of 4-(2-chloro-ethyl)benzoic acid, 1.11 ml of Et₃N and 6.1g of BOP is prepared and stirred for 48 hours. The reaction medium isdiluted with EtOAc and then washed with saturated Na₂CO₃ solution(twice) and with saturated NaCl solution, and then dried over MgSO₄ andconcentrated to dryness. After trituration from EtOH, the insolublematerial formed is removed by filtration and the filtrate is thenconcentrated to dryness to give 7.7 g of the expected compound. Thiscompound is purified by chromatography on silica, eluting with atoluene/cyclohexane gradient (9/1; v/v) up to pure toluene.

By working as described above, the compounds of formula (XXIX) describedin the table below are prepared.

TABLE 4 (XXIX)

Preparation n R₁ R₂ Characterization 4.3.1 2 MeO- nBu NMR 4.3.2 2 MeO-Et NMR 4.3.3 2 MeO- nPrO MH⁺ = 431.2 t = 9.91 4.3.4 1 MeO- nBu — 4.3.5 1MeO- Et m.p. = 141° C.

NMR: Preparation 4.3.1.: 0.85 ppm:t:3H, 1.05-1.6 ppm:m:4H, 2.5-2.6ppm:m:2H, 3.0 ppm:m:2H, 3.8-4.0 ppm:m:5H, 7.0 ppm:m:2H, 7.4-7.6ppm:d:2H, 7.7 ppm:s:1H; 8.0 ppm:m:3H, 12.6 ppm:bs:1H.

NMR: Preparation 4.3.2.: 1.2 ppm:t:3H, 2.7 ppm:q:2H, 3.2 ppm:t:2H, 4.0ppm:m:5H, 7.0-7.2 ppm:m:2H, 7.6 ppm:d:2H, 7.8 ppm:s:1H; 8.0-8.3ppm:m:3H, 12.7 ppm:bs:1H.

Preparation 4.4.1N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-(3-oxopropyl)benzamide

R₁=2-OMe; R₂=5-nBu; R′₃=4-(CH₂)₂CHO

A) N-(-4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-iodobenzamide

A mixture containing 6.62 g of aminothiazole from Preparation 1.2, 75 mlof CH₃CN, 7.53 g of 4-iodobenzoic acid, 4.2 ml of Et₃N and 13.45 g ofBOP is stirred at room temperature for 8 hours. The product formed isfiltered off and then rinsed with CH₃CN. The precipitate is redissolvedin DCM, washed with 7% NaOH solution (twice) and then dried over MgSO₄and evaporated. In parallel, the filtrate in CH₃CN is evaporated, takenup in DCM and then washed 4 times with 7% NaOH solution and dried overMgSO₄. A total of 16.81 g of expected compound are thus obtained.MH⁺=492; t=12.01 minutes.

B)N-(4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl)-4-(3-oxopropyl)benzamide

2 g of the compound from the preceding step are placed in 15 ml of DMFwith 0.79 g of 4 Å molecular sieves, 0.42 ml of allyl alcohol, 1.31 g ofdried tetra(n-butyl)ammonium bromide and 0.85 g of dried NaHCO₃. Afterstirring for 2 hours at room temperature, 50 mg of Pd(OAc)₂ are addedand stirring is continued at room temperature for 20 hours, under drynitrogen. The resulting mixture is filtered through Celite® and rinsedwith DMF, and then water and ether are added. After separation of thephases by settling, the aqueous phase is extracted a further 3 timeswith ether. The combined organic phases are dried over MgSO₄ andevaporated under vacuum. 2 g of the expected compound are obtained.

By working as described above, the compounds of formula (XXVII) and theiodo precursors thereof as described in step A of the above preparationare prepared.

TABLE 5

Preparation No. R₁ R₂ R Characterization OMe nBu I MH⁺ = 493.2 t = 12.014.4.1 OMe nBu —(CH₂)₂CHO — OEt Et I m.p. = 180° C. 4.4.2 OEt Et—(CH₂)₂CHO — OMe Et I MH⁺ = 465.1 t = 11.35 4.4.3 OMe Et —(CH₂)₂CHO —

Preparation 4.5N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-N′-(2-oxoethyl)terephthalamidehydrochloride

(XXXIVa), HCl: R₁=2-OMe; R₂=5-OnPr; R′₃=4-CONHCH₂CHO

A)N-(2,2-Dimethoxyethyl)-N′-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)terephthalamide

A mixture containing 2.6 g of the compound from Preparation 4.2.3, 30 mlof CH₃CN, 1.61 ml of Et₃N, 0.53 ml of aminoacetaldehyde dimethyl acetaland 2.56 g of BOP is stirred at room temperature for three and a halfhours. After filtration, the filtercake is washed with CH₃CN and thenwith DCM. The filtrate is evaporated and the residue is triturated withCH₃CN and filtered to give 2 g of the expected compound.

B)N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-N′-(2-oxoethyl)terephthalamidehydrochloride

0.2 g of the compound obtained in the preceding step are placed in 2 mlof dioxane under dry nitrogen, the mixture is heated to reflux fordissolution and cooled to RT, followed by addition of 3 ml of 4M HCl indioxane, and this mixture is stirred for 7 hours. The precipitate formedis filtered off under nitrogen to give 0.15 g of the expected compound.

Preparation 4.64-(2-Hydroxyethoxy)-N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)benzamide

(XVIII): R₁=2-OMe; R₂=5-OnPr; R′₃=4-O(CH₂)₂OH.

A) Methyl 4-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)benzoate

A mixture containing 40 g of methyl 4-hydroxybenzoate and 90.84 g ofK₂CO₃ in 400 ml of DMF is heated to 100° C. and 71.47 g of2-(2-bromoethoxy)tetrahydro-2H-pyran are added slowly, with continuedheating for 8 hours. The inorganic material is filtered off and rinsedwith DMF. The filtrate is evaporated under vacuum and then taken up inDCM, washed 3 times with water, dried over MgSO₄ and then evaporated.77.66 g of the expected compound are obtained.

B) 4-(2-(Tetrahydro-2H-pyran-2-yloxy)ethoxy)benzoic acid

A mixture containing 77.66 g of the product from the preceding step in400 ml of MeOH and 135 ml of 5M NaOH is stirred at RT, under drynitrogen, for one day. The reaction medium is evaporated and then takenup in water and acidified to pH=5 by addition of HCl. The resultingmixture is filtered and then rinsed with water. The filtrate isextracted twice with DCM and then dried over MgSO₄ and evaporated. 72 gof the expected compound are obtained.

C)N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(tetrahydro-2H-pyran-2-yloxy)ethoxy)benzamide

(XVII): R′₃=4-O(CH₂)₂—OTHP.

A mixture containing 3.83 g of the compound from Preparation 1.1, 30 mlof CH₃CN, 4.63 g of acid obtained from the preceding step, 7.69 g of BOPand 2.4 ml of Et₃N is stirred at RT for 4 days. The precipitate formedis filtered off, rinsed with CH₃CN and dried over P₂O₅ at 60° C. 5.5 gof the expected compound are obtained, m.p.=114° C.

D)4-(2-Hydroxyethoxy)-N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)benzamide

5.41 g of the compound from the preceding step are placed in 25 ml of 4MHCl in dioxane and are stirred for 30 minutes. The precipitate formed isfiltered off and then rinsed with dioxane and with ether and dried overP₂O₅ at 60° C. 4.6 g of the expected compound are obtained.

Preparation 4.7N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(2-oxoethoxy)benzamide

(XIV): R₁=OMe; R₂=OnPr; R′₃=4-OCH₂CHO.

A)4-(2,2-Diethoxyethoxy)-N-(4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)benzamide

A mixture containing 4.56 g of the compound from Preparation 1.1 and5.26 g of the benzoic acid derivative from Preparation 3.1 in 40 ml ofCH₃CN is stirred for 3 days with 9.16 g of BOP and 2.9 ml of Et₃N. Afterevaporation, the residue is taken up in DCM and then washed 3 times withwater, dried over MgSO₄ and evaporated. The product obtained ischromatographed on silica, eluting with a toluene/EtOAc mixture (95/5;v/v). The product is taken up in ether, filtered off, rinsed and thendried at 60° C. over P₂O₅ to give 6.12 g of the expected compound.m.p.=107° C.

B)N-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(2-oxoethoxy)benzamide

1.52 g of the compound from the preceding step are placed in 3.8 ml offormic acid and heated at 50° C. for 3 hours. After cooling to roomtemperature, water is added and the mixture is then filtered, rinsedwith water and dried at 60° C. over P₂O₅. 1.25 g of the expectedcompound are obtained.

Preparation 4.7aN-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(2-oxoethoxy)benzamide

A mixture containing 0.4 g of the compound from Preparation 4.6 in 0.36ml of DMSO and 5 ml of DCM is cooled to −60° C. under dry nitrogen andstirred for 2 hours. 0.83 ml of Et₃N is added and the temperature isallowed to return to RT. The inorganic material is filtered off and thenrinsed with DCM. The filtrate is washed with water, with 10% Na₂CO₃solution and then twice with saturated NaCl solution. The resultingsolution is dried over MgSO₄ and evaporated. 0.39 g of the expectedcompound is obtained.

Preparation 4.82-(4-(((4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)amino)carbonyl)phenoxy)ethylmethanesulphonate

A mixture containing 0.4 g of the compound from Preparation 4.6 in 5 mlof DCM, 0.28 ml of Et₃N and 120 μl of CH₃SO₂Cl is prepared. This mixtureis stirred for one and a half hours while cooling in an ice bath. Theinsoluble material is filtered off and rinsed with DCM. The filtrate iswashed 3 times with water. The organic phase is dried over MgSO₄,filtered, rinsed with DCM and evaporated to give 0.38 g of the expectedcompound.

EXAMPLE 1 Compound 65N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4((4-[2-(S)-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl)carbonyl)benzamide

A solution containing 82 mg of the compound of Preparation 4.1.1 and 45mg of (S)-prolinol in 2 ml of DCM and drops of CH₃CO₂H is stirred for 30minutes, 100 mg of NaBH(OAc)₃ are then added and the mixture is stirredfor 12 hours. The medium is diluted with 200 ml of EtOAc and then washedtwice with Na₂CO₃, dried over MgSO₄ and evaporated. The product obtainedis ultrasonicated in the presence of 5 ml of ether and then filtered togive 70 mg of the expected compound. m.p.=199° C.

NMR spectrum: 0.85 ppm:t:3H, 1.1-2 ppm:m:12H, 2.2-4.6 ppm:m:15H, 6.8-7.2ppm:dd:2H, 7.45 ppm:d:2H, 7.65 ppm:s:1H; 7.95 ppm:s:1H; 8.1 ppm:d:2H,12.6 ppm:bs:1H.

EXAMPLE 2 Compound 1204-((4-[3-(R)-(Acetylamino)pyrrolidin-1-yl]piperidin-1-yl)carbonyl)-N-[4-(5-butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]benzamide

A mixture containing 0.25 g of the compound of Preparation 4.1.1, 0.13 gof (3R)-3-acetamidopyrrolidine and 2 ml of DCM is placed under drynitrogen and stirred for 15 minutes, followed by addition of 0.22 g ofNaBH(OAc)₃ and 8 drops of AcOH, and stirring is continued at roomtemperature for 3 hours 50 minutes. 10% Na₂CO₃ solution and EtOAc areadded. After separation of the phases by settling, the organic phase iswashed with 10% Na₂CO₃ and then dried over MgSO₄ and then evaporated.The residue is triturated in ether and then filtered, rinsed with etherand dried at 60° C. over P₂O₅. 0.25 g of the expected compound isobtained. m.p.>200° C. dec.

NMR spectrum: 0.85 ppm:t:3H; 1-2.1 ppm:m:13H, 2.1-4.5 ppm:m:15H, 6.8-7.2ppm:dd:1H; 7.45 ppm:d:2H, 7.65 ppm:s:1H; 7.85 ppm:d:1H; 8.15 ppm:d:2H,12.65 ppm:bs:1H.

EXAMPLE 3 Compound 107N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-((4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl)benzamidedihydrochloride

A mixture containing 0.6 g of the compound of Preparation 4.2.1, 6 ml ofCH₃CN, 0.31 ml of ethyldiiso-propylamine, 0.27 g of4-(pyrrolidin-1-yl)piperidine in 2 ml of CH₃CN and 0.78 g of BOP isstirred at room temperature for 9 days. After evaporating off thesolvents, the medium is taken up in EtOAc and then washed with aqueous10% Na₂CO₃ solution (3 times), then with saturated NaCl solution andthen dried over MgSO₄ and evaporated under vacuum. The residue ischromatographed on silica, eluting with DCM/MeOH (100/3; v/v) to give0.43 g of base, m.p.=128° C., MH⁺=547.4; t=6.83.

The base obtained is taken up in DCM, followed by addition ofhydrochloric ether. 0.44 g of the expected compound is obtained afterfiltration and drying.

NMR spectrum: 0.85 ppm:t:3H, 1.05-2 ppm:m:12H, 2.25 ppm:m:1H; 2.5ppm:t:2H, 2.8-4.40 ppm:m:12H, 6.95 ppm:d:1H; 7.05 ppm:dd:1H; 7.5ppm:d:2H, 7.65 ppm:s:1H; 7.95 ppm:d:1H; 8.15 ppm:d:1H; 12.55 ppm:bs:1H.

EXAMPLE 4 Compound 68N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-((4-(tetrahydro-2H-pyran-4-ylamino)piperidin-1-yl)carbonyl)benzamidedihydrochloride A)

0.3 g of the compound of Preparation 4.2.1 is placed in 3 ml of CH₃CN,and 153 μl of ethyldiisopropylamine, 0.25 g of amine from Preparation2.1 and 0.39 g of BOP are added. The mixture is stirred at roomtemperature overnight and then filtered, rinsed with ether and driedover P₂O₅ at 60° C. 0.36 g of the expected compound is obtained.m.p.=152° C.

B)

0.35 g of the compound from the preceding step is placed in 3 ml of 4MHCl in dioxane and stirred for 35 minutes at room temperature. Ether isadded and the mixture is filtered, washed with ether and then dried overP₂O₅ at 60° C. 0.32 g of the expected compound is obtained. m.p.=181° C.

NMR spectrum: 0.85 ppm:t:3H, 1.25 ppm:sext:2H, 1.15-1.90 ppm:m:10H, 2.5ppm:t:2H, 2.65-4.70 ppm:m:15H, 6.95 ppm:d:1H; 7.05 ppm:dd:1H; 7.45ppm:d:2H, 7.65 ppm:s:1H; 7.95 ppm:d:1H; 8.1 ppm:d:2H, 9.3 ppm:bs:1H;12.65 ppm:bs:1H.

Starting with the intermediate compounds described in the table below,the process is performed according to Example 4, step B by treatment inacidic medium, to prepare compounds of formula (I) according to theinvention.

TABLE 6 (IV)

Preparation R₂ R′₃ Characterization 5.1 -nBu

m.p. = 152° C. 5.2 -Et Boc-NH—(CH₂)₂—NHCO— m.p. = 221° C. 5.3 -OnPr

MH⁺ = 581.4 t = 10.12 5.4 -OnPr

MH⁺ = 581.4 t = 9.74 5.5 -nBu

MH⁺ = 566.4 t = 12.11 5.6 -nBu

MH⁺ = 552.5 t = 11.84 5.7 -nBu

MH⁺ = 566.5 t = 12.37 5.8 -nBu

MH⁺ = 591.4 t = 10.63 m.p. = 115° C. 5.9 -nBu

m.p. = 98° C. 5.10 Cyclopentyl

m.p. = 180° C. 5.11 -nBu

m.p. = 82° C. 5.12 -nPr

MH⁺ = 596.3 t = 10.74 5.13 -nBu

MH⁺ = 579 t = 10.6 5.14 -nBu

MH⁺ = 579 t = 10.6

EXAMPLE 4a Compound 68N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-((4-(tetrahydro-2H-pyran-4-ylamino)piperidin-1-yl)carbonyl)benzamidedihydrochloride

A)

A mixture containing 370 mg of the compound from Preparation 1.2, 3 mlof CH₃CN, 378 mg of BOP and 151 mg of the compound from Preparation 3.2is stirred at room temperature for 48 hours. The reaction medium isdiluted with EtOAc and then washed 3 times with aqueous 10% Na₂CO₃solution and then 3 times with aqueous NaCl solution. The organic phaseis dried over MgSO₄ and then concentrated to dryness. The residue istaken up in isopropyl ether and then filtered and dried to give 325 mgof the expected compound. m.p.=152° C.

B)

320 mg of the compound from the preceding step in 3 ml of 4M HCl indioxane are stirred for one hour. Ether is added, the mixture isfiltered and the solid is then washed with ether and dried to give 259mg of the expected compound. m.p.=181° C.

EXAMPLE 5 Compound 1614-[3-(3-(Acetylamino)pyrrolidin-1-yl)propanoyl]-N-[4-(5-butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]benzamide

A mixture containing 0.3 g of the compound from Preparation 4.3.1, 0.12g of KI, 0.06 g of NaHCO₃ in 3 ml of DMF and 897.3 mg ofpyrrolidine-3-acetamide is stirred at 50° C. for 2 days. The medium isconcentrated to dryness and then taken up in DCM. The organic phase iswashed twice with saturated NaCl solution and then dried over MgSO₄ andconcentrated to dryness. The product crystallizes out in the presence ofMTBE. After filtration and drying, 0.02 g of the expected compound isobtained, m.p.=112° C.

EXAMPLE 6 Compound 185N-[4-(5-Ethyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-[N-((1-ethylpyrrolidin-2-yl)methyl)glycyl]benzamidetrihydrochloride

A mixture containing 0.25 g of the compound from Preparation 4.3.5 in 3ml of CH₃CN and 0.21 g of 2-aminomethyl-1-ethylpyrrolidine in 1 ml ofCH₃CN is refluxed for five and a half hours. After stirring overnight atroom temperature, the mixture is evaporated and the residue is taken upin DCM and then washed 3 times with water, dried over MgSO₄ andevaporated. The product obtained is chromatographed on silica, elutingwith DCM/MeOH (100/5; v/v).

The compound obtained is taken up in DCM, hydrochloric ether is addedand the precipitate formed is then filtered off and rinsed with ether.It is dried over P₂O₅ at 60° C. to give 0.17 g of the expected compound,m.p.=163° C. (dec).

EXAMPLE 7 Compound 182N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-[3-(tetrahydro-2H-pyran-4-ylamino)propyl]benzamide

A mixture containing 0.38 g of the compound from Preparation 4.4.1 in 3ml of DCM and 0.15 g of 4-aminotetrahydropyran in 1 ml of DCM is placedunder nitrogen. After stirring for 15 minutes, 0.31 g of NaBH(OAc)₃ isadded and stirring is continued for 6 hours. 10% Na₂CO₃ solution andEtOAc are added, the phases are then separated by settling and theorganic phase is washed with 10% Na₂CO₃ solution and then dried overNa₂SO₄ and evaporated. The product obtained is chromatographed onsilica, eluting with DCM/MeOH (100/4; v/v). 0.11 g of the expectedcompound is obtained.

EXAMPLE 8 Compound 95N-[4-(5-Ethyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-N′-(2-pyrrolidin-1-ylethyl)terephthalamide

A mixture containing 0.3 g of the compound from Preparation 4.2.14, 3 mlof CH₃CN, 0.25 ml of ethyldiisopropylamine, 98 mg of1-(2-aminoethyl)pyrrolidine in 2 ml of CH₃CN, 0.38 g of BOP and 1 ml ofDMF is stirred at room temperature for 2 days. The product is filteredoff, rinsed with CH₃CN and then dried at 60° C. over P₂O₅. 0.22 g of theexpected compound is obtained. m.p.=170° C.

EXAMPLE 9 Compound 94-[2-(2-(S)-(Hydroxymethyl)pyrrolidin-1-yl)ethoxy]-N-[4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl]benzamide

A mixture containing 0.2 g of Preparation 4.7, 3 ml of DCM, 112 μl of(S)-(+)-2-pyrrolidinemethanol, 0.2 g of NaBH(OAc)₃ and 5 drops ofCH₃CO₂H is stirred for 18 hours. Saturated Na₂CO₃ solution, water andDCM are added to the reaction medium and the phases are then separatedby settling. The organic phase is washed with water and then dried overMgSO₄ and evaporated. The residue is purified by chromatography onsilica, eluting with a DCM/MeOH mixture (100/2, v/v). 100 mg of theexpected compound are obtained.

MH⁺=511; t=5.72 minutes

[α]_(D) ²⁰=−11.2° (c=0.848, DMSO)

EXAMPLE 10 Compound 183N-[4-(5-Butyl-2-methoxyphenyl)-1,3-thiazol-2-yl]-4-[(4-tetrahydro-2H-pyran-4-ylamino)piperidin-1-yl)methyl]benzamideA)

A mixture containing 0.25 g of the compound from Preparation 4.3.4 and0.34 g of the compound from Preparation 2.1 in 1 ml of CH₃CN is refluxedfor one hour. The product is filtered off, rinsed with CH₃CN and thenwith ether and dried at 60° C. over P₂O₅. 0.35 g of the expectedcompound is obtained.

B)

0.34 g of the compound obtained in the preceding step is placed in 3 mlof 4M HCl/dioxane and stirred for 5 hours at room temperature. Water isadded and the product is filtered and then rinsed with ether and driedover P₂O₅ at 60° C. The resulting solid is taken up in an EtOAc/10%Na₂CO₃ mixture. After separation of the phases by settling, the organicphase is washed with 10% Na₂CO₃ and then with water, dried over MgSO₄and then evaporated. The residue is purified by chromatography onsilica, eluting with DCM/MeOH (90/3; v/v). 93 mg of the expectedcompound are obtained.

MH⁺=562, t=5.8 minutes.

EXAMPLE 11 Compound 17N-[2-(2-(S)-(Hydroxymethyl)pyrrolidin-1-yl)ethyl]-N′-[4-(2-methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl]terephthalamide

0.13 g of the compound from Preparation 4.5 in 2 ml of DCM is mixed with54 mg of (S)-(+)-2-pyrrolidinemethanol, under dry nitrogen. Afterstirring for 15 minutes, 107 mg of NaBH(OAc)₃ and 5 drops of AcOH areadded and stirring is continued for 4 hours. Saturated Na₂CO₃ solution,water and DCM are added to the reaction medium and the phases are thenseparated by settling. The aqueous phase is re-extracted with DCM andthe extracts are washed twice with saturated NaCl solution. The organicphases are combined and dried over MgSO₄. After partial evaporation,CH₃CN and ether are added and the precipitate formed is filtered off anddried at 45° C. over P₂O₅. 57 mg of the expected compound are obtainedin solid form. m.p.=168° C. (dec.).

EXAMPLE 12 Compound 14aN-(4-(2-Methoxy-5-propoxyphenyl)-1,3-thiazol-2-yl)-4-(2-piperidin-1-ylethoxy)benzamidedihydrochloride

A mixture containing 0.19 g of the compound from Preparation 4.8, 62 mgof K₂CO₃ and 38 mg of piperidine in 3 ml of DMF is heated at 80° C. for2 hours 40 minutes. The mixture is allowed to cool to RT and DCM andwater are then added. The reaction medium is washed with water and thenwith dilute NaOH solution. The organic phase is dried over MgSO₄ andevaporated. The residue is chromatographed on silica, eluting withDCM/MeOH (100/2; v/v). The mixture is taken up in DCM followed byaddition of hydrochloric ether, filtering and washing with ether. Afterdrying over P₂O₅ at 60° C., 54 mg of the expected compound are obtained.

NMR spectrum: Compound 14a: 0.97 ppm:t:3H, 1.2-2.0 ppm:m:8H, 2.9-3.1ppm:m:2H, 3.4-3.6 ppm:m:4H, 3.8-4.0 ppm:m:5H, 4.49 ppm:t:2H, 6.88ppm:dd:1H; 7.02 ppm:d:1H; 7.13 ppm:d:2H, 7.74 ppm:s:1H; 7.77 ppm:d:1H;8.17 ppm:d:2H, 10.4 ppm:bs:1H; 12.5 ppm:bs:1H.

EXAMPLE 13 Compound 186 Ethyl(1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)piperidin-4-yl)pyrrolidin-3-yl)carbamate

A) tert-Butyl(1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)piperidin-4-yl)pyrrolidin-3-yl)carbamate

0.3 g of (3R)-3-(tert-butoxycarbonylamino)pyrrolidone is added to asolution of 0.4 g of the compound from Preparation 4.1.1 in 3 ml ofdichloroethane, followed by addition of 0.35 g of NaHB(OAc)₃. 3 drops ofacetic acid are added to the reaction medium, which is then stirred atRT for 2 hours. The medium is hydrolyzed by addition of water and thendiluted with dichloromethane and washed 3 times with 1M sodiumhydroxide. The organic phase is washed with saturated NaCl solution,dried over MgSO₄ and then evaporated to give 0.37 g of the expectedcompound. The crude product thus obtained may be used without furtherpurification in the following step. m.p.=104° C. for a fraction of crudeproduct purified by flash chromatography.

B)4-(4-(3-Aminopyrrolidin-1-yl)piperidine-1-carbonyl)-N-(4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)benzamide

3 ml of trifluoroacetic acid are added, at 0° C., to a solution of 2.7 gof compound 151 dissolved in 9 ml of dichloromethane. The mixture isallowed to return to RT. After 2 hours at RT, the medium is evaporatedand then taken up 3 times in dichloromethane and evaporated. The oilobtained is taken up in dichloromethane and then treated with 10% Na₂CO₃solution. The organic phase is washed with 10% Na₂CO₃ solution and thenwith saturated NaCl solution, and then dried over MgSO₄ and evaporatedto give 2.18 g of a beige-coloured solid. The free base is purified bytrituration from a dichloro-methane/methanol mixture to give 1.9 g ofthe expected product. The hydrochloride is obtained by slow addition ofa 2M solution of hydrogenchloride in ether to a solution of the freebase in a chloroform/methanol mixture. The suspension is evaporated andthen dried under vacuum to give 2 g of hydrochloride.

m.p.=188° C.

C) Ethyl(1-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)piperidin-4-yl)pyrrolidin-3-yl)carbamate

0.46 g of ethyl chloroformate is added to a solution of 2 g of compound152 in its basic form in 7 ml of dichloromethane. The medium is cooledto 0° C. 0.7 g of diisopropylethylamine is then added dropwise. Themedium is stirred until it has returned to RT. The medium is hydrolyzedwith water and then diluted with dichloromethane. The organic phase iswashed with molar sodium hydroxide solution, then with water and thenwith saturated NaCl solution. The organic phase is dried over MgSO₄ andthen evaporated. The crude product is purified by flash chromatographyto give 1.7 g of the expected product.

m.p.=126° C.

The solid obtained is dissolved in dichloromethane and then salified byslow addition of a 2M solution of hydrogen chloride in ether. Afterevaporation, 1.72 g of the hydrochloride are collected.

m.p.=178° C.

EXAMPLE 14 Compound 187N-(4-(5-Butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-methanesulphonylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide

57 mg of methanesulphonyl chloride and 0.14 ml of triethylamine areadded to a solution of 0.14 g of compound 152 in its basic form in 2 mlof a 1/1 mixture of ethyl acetate and DMF. After 24 hours at RT, themedium is filtered and then evaporated and taken up in ethyl acetate.The organic phase is washed twice with saturated NaCl solution, driedover MgSO₄ and evaporated. The crude product is purified by flashchromatography to give 65 mg of a white solid.

m.p.=125° C.

EXAMPLE 15 Compound 153N-(4-(5-Butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(3-propionylaminopyrrolidin-1-yl)piperidine-1-carbonyl)benzamide

0.04 g of propionic anhydride and 0.05 ml of triethylamine are added toa solution of 0.1 g of compound 152 in its basic form in 0.5 ml of ethylacetate. After 2 hours at RT, the medium is diluted in dichloromethane.The organic phase is washed with water and with saturated NaCl solution,dried over MgSO₄ and evaporated. The crude product is purified by flashchromatography to give 67 mg of a white solid.

m.p.=128° C.

EXAMPLE 16 Compound 1881-(1-(4-(4-(5-Butyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)benzoyl)piperidin-4-yl)pyrrolidin-3-ylacetate

73 mg of acetic anhydride are added to a solution of 0.2 g of compound66 dissolved in 1 ml of dichloromethane. After 2 hours at RT, a further73 mg of acetic anhydride are added and the mixture is stirred for 12hours at RT. The medium is diluted in dichloromethane. The organic phaseis washed 3 times with 10% Na₂CO₃ solution, then with water and thenwith saturated NaCl solution, and then dried over MgSO₄ and evaporatedto give 194 mg of a white solid.

m.p.=99° C.

EXAMPLE 17 Compound 1894-(4-(1-Acetylpyrrolidin-3-ylamino)piperidine-1-carbonyl)-N-4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)benzamide

A) tert-Butyl3-(1-(4-(4-(5-butyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)benzoyl)piperidin-4-ylamino)pyrrolidine-1-carboxylate

A solution of 0.23 g of (S)-3-amino-1-N-Boc-pyrrolidine and 0.5 g of thecompound from Preparation 4.1.1 in 2 ml of dichloromethane is stirredfor 30 minutes at RT. 0.43 g of NaHB(OAc)₃ and 8 drops of acetic acidare added to the reaction mixture. The reaction medium is then stirredat RT for 4 hours. The medium is hydrolyzed by addition of water andthen diluted with dichloromethane and washed 3 times with molar sodiumhydroxide. The organic phase is washed with saturated NaCl solution,dried over MgSO₄ and then evaporated to give 0.65 g of the expectedcompound. The crude product thus obtained may be used without furtherpurification in the following step.

MH⁺=662 at t=7.3 minutes.

B)N-4-(5-Butyl-2-methoxyphenyl)thiazol-2-yl)-4-(4-(pyrrolidin-3-ylamino)piperidine-1-carbonyl)benzamide

2 ml of hydrochloric ether are added to a solution of 0.61 g of thecompound obtained in the preceding step in 2 ml of dichloromethane.After 4 hours 30 minutes at RT, the medium is evaporated. The crudeproduct is triturated from ether, filtered off, rinsed with ether anddried to give 0.51 g of the expected compound.

MH⁺=562 at t=5.83 minutes.

C)4-(4-(1-Acetylpyrrolidin-3-ylamino)piperidine-1-carbonyl)-N-4-(5-butyl-2-methoxyphenyl)thiazol-2-yl)benzamide

A suspension of 0.5 g of the compound obtained in the preceding step ina dichloromethane/ethyl acetate mixture is treated with 10% Na₂CO₃solution. After separation of the phases by settling, the aqueous phaseis extracted with ethyl acetate and then with dichloromethane. Thecombined organic phases are dried over MgSO₄ and then evaporated.

0.37 g of free base is thus recovered, which is dissolved in 2 ml ofdichloromethane. 0.062 ml of acetic anhydride is added and the mixtureis stirred for 3 hours 30 minutes at RT. The medium is evaporated andthen chromatographed on silica to give 0.3 g of the expected product.

MH⁺=604 at 6.68 minutes.

The tables that follow illustrate the chemical structures and thephysical properties of a few examples of compounds according to theinvention. In these tables:

-   -   in the “salt” column, “-” represents a compound in free base        form, whereas “HCl” represents a compound in hydrochloride form;    -   Me, Et, nPr, iPr, nBu, iBu, tBu and nHex represent,        respectively, the methyl, ethyl, n-propyl, iso-propyl, n-butyl,        iso-butyl, tert-butyl and n-hexyl groups;    -   Ph and Bn represent, respectively, the phenyl and benzyl groups;    -   THP represents tetrahydropyran-4-yl.

The compounds are characterized either by their nuclear magneticresonance (NMR) spectrum, placed at the end of the table, or by theirmelting point (m.p.), or by their mass spectrum: MH⁺ and retention time(t), expressed in minutes.

TABLE 7 (Ia)

Com- pound No. R₁ R₂ R₃ Salt Characterization 1 -OMe -OnPr —O(CH₂)₂NEt₂2HCl NMR 2 -OMe -OnPr

2HCl MH⁺ = 498.4 t = 6.64 3 -OMe -OnPr —(CH₂)₂NH(CH₂)₂OH — MH⁺ = 472.4 t= 6.45 4 -OMe -OnPr

2HCl MH⁺ = 482.3 t = 5.87 5 -OMe -OnPr —O(CH₂)₂NHiPr 2HCl MH⁺ = 470.2 t= 5.84 6 -OMe -OnPr

2HCl MH⁺ = 572.5 t = 7.59 7 -OMe -OnPr

— MH⁺ = 468.4 t = 5.73 8 -OMe -OnPr

— MH⁺ = 512.4 t = 5.64 9 -OMe -OnPr

— MH⁺ = 512.4 t = 5.72 10 -OMe -OnPr

2HCl MH⁺ = 512.3 t = 5.71 11 -OMe -OnPr —O(CH₂)₂NH-THP 2HCl MH⁺ =512.3 t= 5.75 12 -OEt -OEt —O(CH₂)₂NEt₂ 2HCl MH⁺ = 484.4 t = 5.94 13 -OMe -OnPr

2HCl m.p. = 122° C. (dec) MH⁺ = 525.5 t = 6.84 14 -SEt -nBu —O(CH₂)₂NEt₂2HCl MH⁺ = 512.5 t = 7.64 14a -OMe -OnPr

2HCl NMR 15 -OMe -OnPr —CONH(CH₂)₂NEt₂ — m.p. = 204° C. MH^(+ = 511.4) t= 5.70 16 -OMe -OnPr —CONH(CH₂)₃NEt₂ — MH⁺ = 525.3 t = 5.73 17 -OMe-OnPr

— m.p. = 168° C. MH⁺ = 539.3 t = 5.68 18 -OMe -OnPr

— m.p. = 166° C. MH⁺ = 523.3 t = 5.86 19 -OMe -OnPr

2HCl MH⁺ = 525.5 t = 6.55 20 -OMe -OnPr

2HCl MH⁺ = 539.5 t = 6.55 21 -OMe -OnPr

— MH⁺ = 523.3 t = 5.56 22 -OMe -OnPr

2CF₃—CO₂H MH⁺ = 481.5 t = 6.28 23 -OMe -OnPr

— m.p. = 153° C. MH⁺ = 579.5 t = 6.32 24 -OMe -OnPr

— m.p. = 205° C. MH⁺ = 579.5 t = 6.31 25 -OMe -OnPr

— m.p. = 205° C. 26 -OMe -OnPr

— m.p. = 178° C. 27 -OMe -OnPr

2CF₃—CO₂H MH⁺ = 481.2 t = 6.30 28 -OMe -OnPr

— m.p. = 152° C. MH⁺ = 523.4 t = 6.52 29 -OMe -OnPr

2HCl MH⁺ = 523.3 t = 6.58 30 -OMe -OnPr

— m.p. = 150° C. MH⁺ = 523.4 t = 6.52 31 -OMe -OnPr

2CF₃—CO₂H MH⁺ = 481.5 t = 6.10 32 -OMe -OnPr

— MH⁺= 481.4 t = 6.25 33 -OMe -OnPr —(CH₂)₂—NEt₂ 2(HO₂C—CO₂H) NMR 34-OMe -OnPr

— m.p. = 141° C. 35 -OMe -nBu —O(CH₂)₂NEt₂ 2HCl MH⁺= 482.4 t = 6.46 36-OMe -nPr —O(CH₂)₂NEt₂ 2HCl MH⁺= 468.3 t = 6.17 37 -OMe -OEt—O(CH₂)₂NEt₂ 2HCl MH⁺= 454.2 t = 5.84 38 -OMe -nPr

— MH⁺= 466.3 t = 6.12 39 -OMe -nPr —O(CH₂)₂NH-THP 2CF₃—CO₂H MH⁺= 496.3 t= 6.03 40 -OMe -nPr —O(CH₂)₂NMe-THP — MH⁺= 510.4 t = 6.13 41 -OMe -iPr—O(CH₂)₂NEt₂ 2HCl MH⁺= 468.4 t = 6.16 42 -OMe -Ph —O(CH₂)₂NEt₂ 2HCl MH⁺=502.2 t = 7.16 43 -OMe

—O(CH₂)₂NEt₂ 2HCl MH⁺= 508.5 t = 7.41 44 -OMe -Et —O(CH₂)₂NEt₂ 2HCl MH⁺=468.4 t = 6.89 45 -OMe —CF₃ —O(CH₂)₂NEt₂ 2HCl MH⁺= 494.5 t = 6.68 46-OMe -nBu

— MH⁺= 510.4 t = 7.11 47 -OMe

—(CH₂)₂NH-THP 2HCl MH⁺ = 536.4 t = 7.31 48 -OEt tert-Pentyl —(CH₂)₂NEt₂— m.p. = 116° C. MH⁺ = 510.5 t = 7.60 49 -OMe -secBu —(CH₂)₂NEt₂ 2HClm.p. = 150-156° C. MH⁺ = 482.5 t = 7.24 50 -OMe -tertBu —(CH₂)₂NEt₂ 2HClm.p. = 149-151° C. MH⁺ = 482.4 t = 6.05 51 -OMe -nBu

2HCl MH⁺ = 466.3 t = 7.09 52 -OMe -nBu

2HCl MH⁺ = 452.4 t = 7.01 53 -OMe

—(CH₂)₂NEt₂ 2HCl MH⁺ = 494.4 t = 7.23 54 -OMe -nBu

2HCl MH⁺ = 466.4 t = 7.12 55 -OMe —CHEt₂ —(CH₂)₂NEt₂ 2HCl MH⁺ = 496.4 t= 7.29 56 -OMe -nBu

2HCl MH⁺ = 452.4 t = 6.98 57 -OMe

2HCl MH⁺ = 492.4 t = 7.33 58 -OMe —CH-(nPr)₂ —(CH₂)₂NEt₂ 2HCl MH⁺ =524.4 t = 7.84 59

-nBu —(CH₂)₂NEt₂ 2HCl MH⁺ = 522.4 t = 7.81 60 -OMe

2HCl MH⁺ = 506.3 t = 7.53 61 -OMe -nBu

2HCl MH⁺ = 466.3 t = 6.93 62 -OEt -nBu —O(CH₂)₂NEt₂ 2HCl MH⁺ = 496.3 t =7.56 63 -OMe -nBu —O(CH₂)₂NEt₂ 2HCl MH⁺ = 510.3 t = 7.90 64 -OnPr -nBu

— MH⁺ = 523.3 t = 6.22 65 -OMe -nBu

— m.p. = 199° C.MH⁺ = 577.5 t = 6.83 66 -OMe -nBu

— MH⁺ = 563.3 t = 6.84 67 -OMe -nBu

-NMR 160° C. dec MH⁺ = 577.5 t = 6.84; NMR 68 -OMe -nBu

2HCl m.p. = 181-189° C. MH⁺ = 577.5 t = 6.80 69 -OMe -Et

— NMR 70 -OMe -Et

— NMR 71 -OMe -Et

— m.p. = 208° C. MH⁺ = 494 t = 6.39 72 -OMe -Et

— MH⁺ = 549.5 t = 6.35 73 -OMe -Et

— MH⁺ = 549.5 t = 6.35 74 -OMe -nBu

— m.p. = 190° C. MH⁺ = 577.5 t = 6.98 75 -OMe -Et

— m.p. ≅ 140° C. MH⁺ = 535.4 t = 6.27 76 -OMe -Et

— m.p. = 90° C. MH⁺ = 493.4 t = 6.45 77 -OMe -Et

— m.p. ≅ 143° C. MH⁺ = 535.4 t = 6.22 78 -OMe -Et

— m.p. = 225° C. MH⁺ = 576.4 t = 6.16 79 -OMe -Et

— m.p. = 165° C. MH⁺ = 563.4 t = 6.42 80 -OMe -nBu

— m.p. ≅ 129° C. MH⁺ = 563.5 t = 6.68 81 -OMe -nBu

— m.p. = 140° C. MH⁺ = 551.5 t = 6.73 82 -OMe -Me

— m.p. ≅ 155° C. MH⁺ = 521.4 t = 5.87 83 -OMe -nBu

— m.p. ≅ 76° C. MH⁺ = 521.4 t = 7.13 84 -OMe -Me

— m.p. = 198° C. MH⁺ = 535.5 t = 5.96 85 -OMe -Me

— m.p. = 160° C. MH⁺ = 535.5 t = 5.93 86 -OMe -nBu

— m.p. = 170° C. MH⁺ = 577.5 t = 6.80 87 -OMe -nPr

— m.p. = 158° C. MH⁺ = 507.5 t = 6.76 88 -OMe -nPr

— m.p. = 102° C. MH⁺ = 507.4 t = 6.68 89 -OMe -nPr

— m.p. = 160° C. MH⁺ = 507.4 t = 6.79 90 -OMe -nBu

— MH⁺ = 537.5 t = 6.67 91 -OMe -nBu

— m.p. = 208° C. MH⁺ =521.5 t = 7.30 92 -OMe -nBu

— m.p. = 132° C. MH⁺ =521.3 t = 7.04 93 -OMe -Et

— MH⁺ =550.4 t = 6.30 94 -OMe -Et

— MH⁺ =509.4 t = 6.28 95 -OMe -Et

— m.p. = 170° C. MH⁺ =479.5 t = 6.44 96 -OMe -Et —CONH(CH₂)₂NH₂ 2HCl MH⁺=425.4 t = 6.32 97 -OMe -Et —CONH(CH₂)₂NEt₂ 2HCl m.p. = 130° C. dec MH⁺=481.4 t = 6.55 98 -OMe -Et

— m.p. = 146° C. MH⁺ =523.5 t = 6.29 99 -OMe -Et —CONH(CH₂)₂NHCOMe —m.p. > 260° C. MH⁺ =467.4 t = 8.04 100 -OMe -nBu

— m.p. = 177° C. MH⁺ =591.4 t = 5.95 101 -OMe -Et

2HCl MH⁺ =493.5 t = 6.59 102 -OMe -nBu

2HCl m.p. = 187° C. MH⁺ = 535.4 t = 6.12 103 -OMe -nBu

2HCl MH⁺ = 549.5 t = 6.75 104 -OMe -nBu

— m.p. = 207° C. MH⁺ = 604.4 t = 6.74 105 -OMe -nBu

2HCl MH⁺ = 537.4 t = 6.69 106 -OMe -nBu

— MH⁺ = 547.4 t = 6.83 107 -OMe -nBu

2HCl MH⁺ = 547.3 t = 6.93 108 -OMe -nBu

2HCl m.p. = 196° C. MH⁺ = 493.3 t = 6.84 109 -OMe -nBu

2HCl m.p. = 192° C. MH⁺ = 492.4 t = 6.65 110 -OMe -nBu

— MH⁺ = 563.3 t = 6.84 111 -OMe -nBu

— m.p. = 180° C. MH⁺ = 494.3 t = 6.80 112 -OMe -nBu

— MH⁺ = 578.4 t = 6.80 113 -OMe -nBu

— m.p. = 150° C. MH⁺ = 604.4 t = 6.91 114 -OEt -Et

— m.p. = 153° C. MH⁺ = 590.4 t = 6.41 115 -OMe -nBu

— MH⁺ = 630.4 t = 6.74 116 -OEt -Et

2HCl m.p. = 171° C. MH⁺ = 479.4 t = 6.57 117 -OEt -Et

— m.p. = 171° C. MH⁺ = 563.4 t = 6.50 118 -OMe -nBu

— MH⁺ = 547.4 t = 7.18 119 -OEt -Et

2HCl MH⁺ = 533.4 t = 6.75 120 -OMe -nBu

— m.p. = 200° C. dec MH⁺ = 604.5 t = 6.65 121 -OEt -Et

— m.p. = 136° C. MH⁺ = 535.3 t = 6.37 122 -OEt -Et

2HCl m.p. = 145° C. MH⁺ = 479.3 t = 6.52 123 -OEt -Et

— m.p. = 134° C. MH⁺ = 549.3 t = 6.34 124 -OMe -nBu

— MH⁺ = 533.4 t = 6.91 125 -OEt -Et

2HCl m.p. = 136° C. MH⁺ = 507.4 t = 6.75 126 -OMe -nBu

— MH⁺ = 658.3 t = 7.14 127 -OMe -nBu

2HCl MH⁺ = 618.4 t = 6.79 128 -OMe -nBu

2HCl MH⁺ = 564.6 t = 6.69 129 -OEt -Et

— m.p. = 170° C. MH⁺ = 563.4 t = 6.74 130 -OMe -nBu

— m.p. = 222° C. MH⁺ = 507.3 t = 6.80 131 -OEt

— m.p. = 143° C. MH⁺ = 487.5 t = 7.53 132 -OEt

— m.p. = 97° C. MH⁺ = 561.4 t = 7.74 133 -OMe -nBu

— m.p. = 188° C. MH⁺ = 561.4 t = 6.99 134 -OMe

— m.p. = 192° C. MH⁺ = 573.4 t = 7.16 135 -OEt -Et

2HCl MH⁺ = 590.3 t = 6.49 136 -OMe

2HCl MH⁺ = 519.3 t = 7.03 137 -OMe

— m.p. = 104° C. MH⁺ = 547.3 t = 7.18 138 -OMe -nBu

2HCl MH⁺ = 494.3 t = 6.96 139 -OEt

2HCl MH⁺ = 617.3 t = 7.32 140 -OMe

2HCl MH⁺ = 603.3 t = 7.03 141 -OMe -nBu

— MH⁺ = 563.4 t = 6.42 142 -OMe -nBu

— MH⁺ = 591.3 t = 6.84 143 -OMe -nBu

— MH⁺ = 619.4 t = 7.07 144 -OMe

— m.p. = 134° C. MH⁺ = 533.3 t = 7.03 145 -OMe -nBu

2HCl MH⁺ = 493.3 t = 6.81 146 -OMe -nPr

— m.p. = 163° C. MH⁺ = 533.3 t = 6.56 147 -OMe -nBu

— m.p. ≅ 170° C. MH⁺ = 577.3 t = 6.82 148 -OMe

2HCl m.p. ≅ 180° C. MH⁺ = 589.3 t = 6.76 149 -OMe -nHex

2HCl MH⁺ = 605.3 t = 7.35 150 -OMe

— m.p. = 164° C. dec MH⁺ = 630.4 t = 6.97 151 -OMe -nBu

— m.p. = 104° C. MH⁺ = 662.3 t = 7.33 152 -OMe -nBu

3HCl m.p. = 188° C. MH⁺ = 561.9 t = 5.82 153 -OMe -nBu

— m.p. = 128° C. MH⁺ = 618.3 t = 6.84 154 -OMe -nBu

— m.p. = 148° C. MH⁺ = 590.3 t = 6.73 155 -OMe

2HCl MH⁺ = 603.3 t = 7.08 156 -OMe -nBu

— m.p. = 182° C. MH⁺ = 507.4 t = 6.89 157 -OMe -nPr

— m.p. = 230° C. MH⁺ = 590.3 t = 6.39 158 -OMe -nPr

— m.p. = 226° C. MH⁺ = 563.2 t = 6.51 159 -OMe -nBu

— m.p. = 94° C. dec MH⁺ = 603.3 t = 6.86 160 -OMe

— m.p. = 148° C. MH⁺ = 616.3 t = 6.66 161 -OMe -nBu

— m.p. = 112° C. MH⁺ = 521.4 t = 6.98 162 -OMe -Et —(CH₂)₃NEt₂ 2HCl MH⁺= 452.5 t = 6.76 163 -OMe -Et

— MH⁺ = 494.5 t = 6.95 164 -OMe -nBu

— MH⁺ = 480.4 t = 7.18 165 -OMe -nBu

— MH⁺ = 507.5 t = 6.25 166 -OMe -Et

— MH⁺ = 507.6 t = 6.62 167 -OMe -nBu

— MH⁺ = 494.4 t = 7.76 168 -OMe -Et

— MH⁺ = 466.4 t = 6.57 169 -OMe -Et

— MH⁺ = 493.5 t = 6.93 170 -OMe -Et

— MH⁺ = 452.4 t = 6.94 171 -OMe -Et —(CH₂)₃NH(CH₂)₂OH — m.p. = 140° C.dec MH⁺ = 440.4 t = 7.11 172 -OMe -Et —(CH₂)₃NH-THP 2HCl MH⁺ = 480.5 t =6.54 173 -OMe -Et

— MH⁺ = 480.4 t = 6.49 174 -OMe -Et

2HCl MH⁺ = 450.5 t = 6.54 175 -OMe -Et

2HCl MH⁺ = 452.4 t = 6.35 176 -OMe -nBu

2HCl m.p. = 173° C. MH⁺ = 450.4 t = 7.18 177 -OMe -nBu

— MH⁺ = 480.4 t = 7.13 178 -OMe -nBu

— MH⁺ = 494.4 t = 7.04 179 -OMe -nBu

— MH⁺ = 535.4 t = 6.99 180 -OMe -nBu

2HCl m.p. = 220° C. MH⁺ = 450.4 t = 7.19 181 -OEt -Et

— MH⁺ = 521.4 t = 6.63 182 -OMe -nBu —(CH₂)₃NH-THP — m.p. = 150° C. MH⁺= 508.4 t = 7.10 183 -OMe -nBu

— m.p. = 80° C. dec MH⁺ = 563.4 t = 5.80 184 -OMe -nBu

— m.p. = 80° C. dec MH⁺ = 577.3 t = 5.94 185 -OMe -Et

2HCl m.p. = 163° C. dec MH⁺ = 479.4 t = 6.14 186 -OMe -nBu

HCl m.p. = 178° C. MH⁺ = 634 t = 7.03 187 -OMe -nBu

— m.p. = 125° C. MH⁺ = 640 t = 6.88 188 -OMe -nBu

— m.p. = 99° C. MH⁺ = 605 t = 6.92 189 -OMe -nBu

— MH⁺ = 604 t = 6.68 190 -OMe -OnPr

— m.p. = 210° C. 191 -OMe —F —O(CH₂)₂NEt₂ HCl m.p. = 228° C. 192 -OMe-nHex —O(CH₂)₂NEt₂ HCl MH⁺ = 510 t = 7.73 193 -OEt -nHex —O(CH₂)₂NEt₂HCl m.p. = 182° C. MH⁺ = 524 t = 8.05 194 -OMe

—O(CH₂)₂NEt₂ HCl MH⁺ = 560 t = 7.93 195 -OEt -nPr —O(CH₂)₂NEt₂ — MH⁺ =482 t = 7.11 196 -OMe —CF₂CF₃ —O(CH₂)₂NEt₂ — MH⁺ = 544 t = 6.79 197 -OMe

— MH⁺ = 688 t = 7.53 198 -OMe -nBu

— m.p. = 158° C. MH⁺ = 619 t = 7.09 199 -OMe

— MH⁺ = 588 t = 6.06 200 -OMe

— MH⁺ = 643 t = 7.06 201 -OMe -nBu

— MH⁺ = 632 t = 7.01 202 -OMe

— MH⁺ = 602 t = 5.94 203 -OMe -nPr

— MH⁺ = 576 t = 5.64 204 -OMe -nBu

— MH⁺ = 590 t = 5.91 205 -OMe

— MH⁺ = 658 t = 7.28 206 -OEt

— m.p. = 156° C. MH⁺ = 644 t = 7.33 207 -OMe

— m.p. = 121° C. MH⁺ = 646 t = 7.24 208 -OMe -nBu

— m.p. = 158° C. MH⁺ = 604 t = 6.78 209 -OEt

— MH⁺ = 561 t = 7.77 210 -OEt -Et

— m.p. = 125° C. MH⁺ = 533 t = 6.53 211 -OEt -Et

— m.p. = 151° C. MH⁺ = 507 t = 6.75 212 -OEt -Et

— m.p. = 230° C. MH⁺ = 493 t = 6.69 213 -OMe -nBu

— m.p. = 97° C. MH⁺ = 507 t = 6.76 214 -OMe -nBu

— m.p. = 230° C. MH⁺ = 479 t = 6.84 215 -OMe -nBu

— m.p. = 112° C. MH⁺ = 620 t = 6.89 216 -OMe -nBu

— m.p. = 195° C. MH⁺ = 507 t = 6.23 217 -OMe -nBu

— m.p. = 221° C. MH⁺ = 479 t = 6.79 218 -OMe -nBu

— m.p. = 142° C. MH⁺ = 535 t = 9.04 219 -OMe

— m.p. = 190° C. MH⁺ = 561 t = 9.8 220 -OMe

— m.p. = 172° C. MH⁺ = 674 t = 7.38 221 -OMe -nHex

— m.p. = 124° C. MH⁺ = 563 t = 9.96 222 -OEt

— m.p. = 176° C. MH⁺ = 702 t = 7.98 223 -OMe

— m.p. = 189° C. MH⁺ = 574 t = 5.16 224 -OEt

— m.p. = 161° C. MH⁺ = 602 t = 6.39 225 -OMe

— m.p. = 144° C. MH⁺ = 660 t = 7.37 226 -OEt

— m.p. = 136° C. MH⁺ = 674 t = 7.59 227 -OEt

— m.p. = 131° C. MH⁺ = 672 t = 7.52 228 -OEt

— m.p. = 152° C. MH⁺ = 658 t = 7.47 229 -OMe

— m.p. = 163° C. MH⁺ = 630 t = 7.16 230 -OMe

— m.p. = 136° C. MH⁺ = 646 t = 7.09 231 -OMe

— m.p. = 182° C. MH⁺ = 643 t = 7.29 232 -OEt -nBu

— m.p. = 138° C. MH⁺ = 576 t = 6.06 233 -OEt -nBu

— m.p. = 126° C. MH⁺ = 632 t = 7.12 234 -OEt

— m.p. = 126° C. MH⁺ = 644 t = 7.33 235 -OEt

— m.p. = 126° C. MH⁺ = 660 t = 7.51 236 -OEt

— m.p. = 105° C. MH⁺ = 658 t = 7.26 237 -OEt

— m.p. = 121° C. MH⁺ = 630 t = 7.04 238 -OEt -nBu

— m.p. = 102° C. MH⁺ = 648 t = 7.48 239 -OEt -nBu

— m.p. = 129° C. MH⁺ = 646 t = 7.42 240 -OMe -nBu

— m.p. = 124° C. MH⁺ = 630 t = 7.59 241 -OMe -nBu

— m.p. = 135° C. MH⁺ = 632 t = 7.62 242 (4.1.2.) -OMe -OnPr

— m.p. = 196° C. 243 (4.1.6.) -OMe

— m.p. = 186° C. 244 (4.1.7.) -OEt

— m.p. = 236° C. 245 -OMe

— m.p. = 154° C. 246 -OMe

— m.p. = 158° C. 247 -OEt -nBu

— m.p. = 116° C. 248 -OEt -nBu

— m.p. = 118° C. 249 -OEt

— m.p. = 135° C. 250 -OEt

— m.p. = 141° C. 251 -OMe -nBu

— m.p. = 119° C. 252 -OMe -nBu

— m.p. = 109° C. 253 -OMe -nBu

HCl m.p. = 148° C. 254 -OMe -nBu

— m.p. = 118° C. 255 -OMe -nBu

HCl m.p. = 176° C.

NMR spectrum: Compound 1: 0.98 ppm:t:3H, 1.24 ppm:t:6H, 1.72ppm:sext:2H, 3.1-3.3 ppm:m:4H, 3.4-3.6 ppm:m:2H, 3.8-4.0 ppm:m:5H, 4.50ppm:t:2H, 6.87 ppm:dd:1H; 7.04 ppm:d:1H; 7.16 ppm:d:2H, 7.7-7.8ppm:m:2H, 8.16 ppm:d:2H, 10.6 ppm:bs:1H; 12.5 ppm:bs:1H.

NMR spectrum: Compound 33: 1.00 ppm:t:3H, 1.26 ppm:t:6H, 1.74ppm:sext:2H, 2.9-3.5 ppm:m:8H, 3.8-4.0 ppm:m:5H, 6.88 ppm:dd:1H; 7.04ppm:d:1H; 7.5 ppm:d:2H, 7.7-7.8 ppm:m:2H, 8.14 ppm:d:2H.

NMR spectrum: Compound 67: 0.80 ppm:t:3H, 0.95-1.95 ppm:m:12H, 2.45ppm:t:2H, 2.55-4.4 ppm:m:13H, 6.95 ppm:d:1H; 7.05 ppm:dd:1H; 7.45ppm:d:2H, 7.65 ppm:s:1H; 7.90 ppm:s:1H; 8.1 ppm:d:2H.

NMR spectrum: Compound 69: 1.1 ppm:t:3H, 1.15-1.90 ppm:m:4H, 2.20-4.50ppm:m:17H, 6.95 ppm:d:1H; 7.05 ppm:dd:1H; 7.45 ppm:d:2H, 7.60 ppm:s:1H;7.95 ppm:s:1H; 8.1 ppm:d:2H, 12.65 ppm:bs:1H.

NMR spectrum: Compound 70: 0.85-1.95 ppm:m:11H, 2.30-4.4 ppm:m:15H, 6.95ppm:d:1H; 7.05 ppm:dd:1H; 7.40 ppm:d:2H, 7.60 ppm:s:1H; 7.90 ppm:s:1H;8.1 ppm:d:2H.

The compounds according to the invention underwent pharmacological teststo determine their modulatory effect on the activity of the chemokinereceptors.

Chemokines are low molecular weight proteins belonging to the family ofpro-inflammatory cytokines and are involved in the chemotaxis ofleukocytes and endothelial cells. Chemokines control many biologicalprocesses and are associated with inflammatory disorders appearingduring conditions of stress, during injury or infection; modulation ofthe effects of chemokines makes it possible to prevent or treatpathologies such as asthma, arthritis, allergies, autoimmune diseases,atherosclerosis or angiogenesis (C. D. Paavola et al., J. Biol. Chem.,1998, 273, (50), 33157-33165).

Among the chemokines that may be distinguished are hMCP-1 (humanmonocyte chemotactic protein), which belongs to the group of CCchemokines and whose actions are mediated by the CCR2b receptor.

The inhibitory activity of the compounds according to the invention oncells expressing the human CCR2b receptor was measured. Theconcentration of natural agonist hMCP-1 that inhibits 50% (IC₅₀) of theactivity of the CCR2b receptor is 0.57 nM. The compounds according tothe invention have an IC₅₀ value generally of less than 0.1 μM.

For example, compound 12 has an IC₅₀ value of 0.081 μM;

compound 244 has an IC₅₀ value of 0.088 μM;

compound 203 has an IC₅₀ value of 0.093 μM.

The inhibition of chemotaxis was also measured on human THP-1 monocytes(sold by DSMZ-Germany) using a technique adapted from that described byA. Albini et al., Cancer Res., 1987, 47, 3239-3245. Under theseconditions, hMCP-1 has an IC₅₀ value of 6 nM. The compounds according tothe invention have an IC₅₀ value generally of less than 1 μM.

The inhibition of chemotaxis by the compounds according to the inventionis a sign of their antagonist activity on the chemokine receptors and inparticular CCR2b.

It is thus seen that the compounds according to the invention areantagonists of the effect of chemokines, in particular of hMCP-1.

The inhibitory activity of the compounds according to the invention onPBMCs (peripheral blood mononuclear cells) infected with the HIV-1 Balvirus was also measured, according to a technique adapted from thatdescribed by V. Dolle et al., J. Med. Chem., 2000, 43, 3949, 3962.According to this technique, the PMBCs are infected with HIV-1 Bal andthe test compounds are then added to the culture medium for 5 days. Atthe end of this exposure, the content of reverse transcriptase, which iscorrelated with the level of viral replication in the cells, is measuredin the supernatant.

Under these conditions, AZT, a reference molecule which inhibits viralreplication, has an IC₅₀ value of less than 0.1 μM. The compoundsaccording to the invention also have IC₅₀ values generally of less than0.1 μM. For example, compound 104 showed an IC₅₀ value of 0.063 μM.

The compounds according to the invention may thus be used for thepreparation of medicinal products, in particular medicinal products thatare antagonists of the effect of chemokines.

Thus, according to another of its aspects, a subject of the presentinvention is medicinal products comprising a compound of formula (I), oran addition salt thereof with a pharmaceutically acceptable acid, oralternatively a hydrate or a solvate.

These medicinal products find their therapeutic use especially in theprevention and treatment of various pathologies such as:

acute and chronic immunoinflammatory diseases and syndromes, forinstance atherosclerosis, restenosis, chronic pulmonary diseases, inparticular COPD (chronic obstructive pulmonary disease); respiratorydistress syndrome; bronchial hyperactivity; colitis; silicosis; fibroticpathologies, pulmonary fibrosis and cystic fibrosis; viral or bacterialinfections, AIDS, meningitis, malaria, leprosy, tuberculosis, herpes andcytomegalovirus infections; septic shock, septicaemia and endotoxicshock; graft rejection; bone pathologies such as osteoporosis andosteoarthritis; conjunctivitis; atypic or contact dermatitis; eczema,glomerulonephritis; pancreatitis; ulcerative colitis, autoimmunediseases, for instance rheumatoid arthritis, multiple sclerosis,amyotrophic lateral sclerosis, Crohn's disease, lupus erythematosus,scleroderma and psoriasis; Parkinson's disease; Alzheimer's disease;diabetes; cachexia; obesity;

the treatment of pain, in particular neuropathic and inflammatory pain;

allergic diseases, for instance allergic respiratory diseases, asthma,rhinitis, pulmonary hypersensitivity and delayed hypersensitivity;

diseases and disorders in which angiogenic processes are involved, forinstance cancers (intratumoral angiogenesis) and retinal diseases(age-related macular degeneration: ARMD);

cardiac pathologies: haemodynamic shock; cardiac ischaemia;post-ischaemic reinfusion attack; myocardial infarction, coronarythrombosis, cardiac insufficiency and angina pectoris.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions contain aneffective dose of at least one compound according to the invention, or apharmaceutically acceptable salt, a hydrate or solvate of the saidcompound, and also at least one pharmaceutically acceptable excipient.

The said excipients are chosen according to the pharmaceutical form andthe desired mode of administration, from the usual excipients known tothose skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or the possible salt, solvate orhydrate thereof, may be administered in unit administration form, as amixture with standard pharmaceutical excipients, to man and animals forthe prophylaxis or treatment of the above disorders or diseases.

The appropriate unit administration forms comprise oral-route forms suchas tablets, soft or hard gel capsules, powders, granules and oralsolutions or suspensions, sublingual, buccal, intratracheal,intraoccular and intranasal administration forms, forms for inhalation,topical, transdermal, subcutaneous, intramuscular or intravenousadministration forms, rectal administration forms and implants. Fortopical application, the compounds according to the invention may beused in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in the form of a tablet may comprise the followingcomponents:

Compound according to the invention 50.0 mg Mannitol 223.75 mg  Sodiumcroscaramellose  6.0 mg Maize starch 15.0 mgHydroxypropylmethylcellulose 2.25 mg Magnesium stearate  3.0 mg

Via the oral route, the dose of active principle administered per daymay be up to 0.1 to 1000 mg/kg, in one or more dosage intakes.

There may be particular cases in which higher or lower doses aresuitable; such doses do not depart from the context of the invention. Inusual practice, the dosage that is appropriate for each patient isdetermined by a doctor according to the mode of administration, theweight and the response of the said patient.

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or a pharmaceutically acceptablesalt, hydrate or solvate thereof.

1. A process for preparing a compound of formula (I):

wherein: R₁ represents a hydrogen or halogen atom or a (C₁-C₄)alkyl,trifluoroethyl, hydroxyl, (C₁-C₄)alkoxy, trifluoromethoxy,trifluoroethoxy, (C₃-C₈)cycloalkyloxy, allyloxy, cyclopropylmethoxy or(C₁-C₄)alkylthio group; R₂ represents a hydrogen or halogen atom or a(C₁-C₈)alkyl, trifluoroethyl, perfluoro(C₁-C₄)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, (C₁-C₈)alkoxy, trifluoromethoxy, trifluoroethoxy, allyloxy,(C₃-C₈)cycloalkylmethoxy, (C₃-C₈)cycloalkyloxy or (C₃-C₈)cycloalkylmethyl group; R₃ represents —O—(C₂-C₄)alk-A, —O—(C₁-C₄)alk-B,—O-E, —(C₁-C₄)alk-A, —B, —(C₁-C₄)alk-NR₄—(C₂-C₃)alk-A, —(C₁-C₄)alk-NR₄—(C₁-C₃)alk-B, —CONR₄—(C₂-C₄)alk-A, —CONR₄—(C₁-C₄)alk-B, —CONR₄-E,—CO-D-(C₁-C₂)alk-A, —CO-G-A,

R₄ represents a hydrogen atom or a (C₁-C₄)alkyl group; A represents agroup NR₅R₆; B represents a group

D represents a group

E represents a group

G represents a group

R₅ and R₆ each represent, independently of each other, a hydrogen atomor a (C₁-C₆)alkyl, allyl, (C₂-C₄)alk-O—(C₁-C₄)alkyl, (C₂-C₄)alk-OH,(C₁-C₃)alk-CON(R₄)₂, (C₂-C₃) alk-NHCO—(C₁-C₄)alkyl, (C₃-C₇) cycloalkyl,(C₃-C₇)cycloalkylmethyl, —CO—(C₁-C₄)alkyl, benzyl, pyrrolidinyloptionally substituted with a —CO—(C₁-C₄)alkyl group, tetrahydropyranyl,tetrahydropyranylmethyl, dimethyltetrahydropyranyl, tetrahydrofuryl ortetrahydrofurylmethyl group; or R₅ and R₆, together with the nitrogenatom to which they are attached, constitute a heterocyclic radicalselected from the group consisting of aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, morpholinyl, piperazinyl,tropanyl, quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl, and2-aza-bicyclo[2,2,2]octanyl, the said heterocyclic radicals beingunsubstituted or substituted with a phenyl, halophenyl,trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy,hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino group, agroup —NR₄R₇, tetrahydropyran-4-ylamino, —CON(R₄)₂, —CONR₄R′₄,—CH₂CON(R₄)₂, (C₁-C₄)alkyl-CONR₄—, (C₃-C₈)cycloalkyl-CONR₄—,(C₁-C₄)alkyl-OCONR₄—, (C₃-C₈)cycloalkyl-OCONR₄—, ((C₁-C₄)alkyl-OCO)₂N—or (C₁-C₄)alkyl-COO—, or substituted with one or more methyl groups; R′₄represents a group (CH₂), linked to the carbon atom bearing —CONR₄R′₄;R₇ represents a hydrogen atom, a (C₁-C₄)alkyl or an —SO₂CH₃ group or R₄and R₇, together with the nitrogen atom to which they are attached,constitute a pyrrolidinyl or piperidinyl radical; p represents 1, 2, 3,4 or 5; q represents 0, 1 or 2; r represents 1 or 2; s represents 2 or3; p+q being less than or equal to 5; p+r being less than or equal to 5;and alk represents an alkylene; provided that R₁ and R₂ are notsimultaneously a hydrogen atom; comprising (a) treating a functionalderivative of an acid of formula (II)

where R′₃ represents R₃, or a precursor of R₃, with a 2-aminothiazolederivative of formula (III),

where R′₁ and R′₂ represent, respectively, R₁ and R₂, or precursors ofR₁ and R₂; to obtain a compound of formula (IV),

where R′₁, R′₂ and R′₃ are, respectively, R₁, R₂ or R₃, or precursors ofR₁, R₂ and R₃; and (b) converting the compound of formula (IV), whereappropriate, to a compound of formula (I).
 2. A compound of formula(IIb),

or a (C₁-C₄) aliphatic ester or benzyl ester of a compound of formula(IIb), where the phenyl portion of the benzyl portion of the benzylester is unsubstituted, or substituted with a methoxy group, wherein:R′₃ represents a group(C₁-C₄)alk-A or a group -B, where A represents agroup NR₅R₆; and B represents a group

R₅ and R₆ each represent, independently of each other, a hydrogen atomor a (C₁-C₆)alkyl, allyl, (C₂-C₄)alk-O—(C₁-C₄) alkyl, (C₂-C₄) alk-OH,(C₁-C₃) alk-CON(R₄)₂, (C₂-C₃) alk-NHCO— (C₁-C₄) alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkylmethyl, —CO— (C₁-C₄)alkyl, benzyl,pyrrolidinyl optionally substituted with a —CO—(C₁-C₄)alkyl group,tetrahydropyranyl, tetrahydropyranylmethyl, dimethyltetrahydropyranyl,tetrahydrofuryl or tetrahydrofurylmethyl group; or R₅ and R₆, togetherwith the nitrogen atom to which they are attached, constitute aheterocyclic radical selected from the group consisting of aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, morpholinyl,piperazinyl, tropanyl, quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl, and2-azabicyclo[2,2,2]octanyl, the said heterocyclic radicals beingunsubstituted or substituted with a phenyl, halophenyl,trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy,hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino group, agroup —NR₄R₇, tetrahydropyran-4-ylamino, —CON(R₄)₂, —CONR₄R′₄,—CH₂CON(R₄)₂, (C₁-C₄)alkyl-CONR₄—, (C₃-C₈)cycloalkyl-CONR₄—, (C₁-C₄)alkyl-OCONR₄—, (C₃-C₈)cycloalkyl-OCONR₄—, ((C₁-C₄)alkyl-OCO)₂N— or(C₁-C₄)alkyl-COO—, or substituted with one or more methyl groups; R₄represents a hydrogen atom or a (C₁-C₄) alkyl group; R′₄ represents agroup (CH₂), linked to the carbon atom bearing —CONR₄R′₄; R₇ representsa hydrogen atom, a (C₁-C₄)alkyl or an —SO₂CH₃ group or R₄ and R₇,together with the nitrogen atom to which they are attached, constitute apyrrolidinyl or piperidinyl radical; p represents 1, 2, 3, 5 or 5; qrepresents 0, 1 or 2; s represents 2 or 3; p+q being less than or equalto 5; and alk represents an alkylene; or R′₃ represents a precursor of agroup (C₁-C₄)alk-A or a group —B, in which any amine or hydroxylfunctions on (C₁-C₄)alk-A or —B that may be present are protected;provided that when (C₁-C₄)alk represents a methylene, B is other thanpiperidinyl.
 3. A compound of the formula (IIe),

or a (C₁-C₄) aliphatic ester or benzyl ester of a compound of formula(IIe), where the phenyl portion of the benzyl portion of the benzylester is unsubstituted, or substituted with a methoxy group, wherein:R′₃ represents —CONR₄—(C₁-C₄)alk-B, —CONR₄-E, —CO-D-(C₁-C₂) alk-A,—CO-G-A,

where A represents a group NR₅R₆; B represents a group

D represents a group

E represents a group

G represents a group

R₅ and R₆ each represent, independently of each other, a hydrogen atomor a (C₁-C₆)alkyl, allyl, (C₂-C₄)alk-O—(C₁-C₄)alkyl, (C₂-C₄)alk-OH,(C₁-C₃)alk-CON(R₄)₂, (C₂-C₃) alk-NHCO—(C₁-C₄)alkyl, (C₃-C₇) cycloalkyl,(C₃-C₇)cycloalkylmethyl, —CO—(C₁-C₄)alkyl, benzyl, pyrrolidinyloptionally substituted with a —CO—(C₁-C₄)alkyl group, tetrahydropyranyl,tetrahydropyranylmethyl, dimethyltetrahydropyranyl, tetrahydrofuryl ortetrahydrofurylmethyl group; or R₅ and R₆, together with the nitrogenatom to which they are attached, constitute a heterocyclic radicalselected from the group consisting of aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, morpholinyl, piperazinyl,tropanyl, quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl, and2-azabicyclo[2,2,2]octanyl, the said heterocyclic radicals beingunsubstituted or substituted with a phenyl, halophenyl,trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy,hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino group, agroup —NR₄R₇, tetrahydropyran-4-ylamino, —CON(R₄)₂, —CONR₄R′₄,—CH₂CON(R₄)₂, (C₁-C₄)alkyl-CONR₄—, (C₃-C₈)cycloalkyl-CONR₄—, (C₁-C₄)alkyl-OCONR₄—, (C₃-C₈) cycloalkyl-OCONR₄—, ((C₁-C₄) alkyl-OCO)₂N— or(C₁-C₄)alkyl-COO—, or substituted with one or more methyl groups; R₄represents a hydrogen atom or a (C₁-C₄) alkyl group; R′₄ represents agroup (CH₂)_(s) linked to the carbon atom bearing —CONR₄R′₄; R₇represents a hydrogen atom, a (C₁-C₄)alkyl or an —SO₂CH₃ group or R₄ andR₇, together with the nitrogen atom to which they are attached,constitute a pyrrolidinyl or piperidinyl radical; p represents 1, 2, 3,5 or 5; q represents 0, 1 or 2; r represents 1 or 2; s represents 2 or3; p+q being less than or equal to 5; p+r being less than or equal to 5;and alk represents an alkylene; or R′₃ represents a precursor of R₃ asdefined in this claim 14, in which any amine or hydroxyl functions on R₃that may be present are protected.
 4. A benzoic acid compound of theformula

or a (C₁-C₄) alkyl ester or benzyl ester of such benzoic acid compound,where the phenyl portion of the benzyl portion of the benzyl ester isunsubstituted, or substituted with a methoxy group, wherein: G′prepresents hydrogen or a protecting group for nitrogen selected from thegroup consisting of Boc, Fmoc, benzyloxycarbonyl, benzyl and(C₁-C₄)alkanoyl.
 5. A compound of the formula

wherein the amine functions are free or protected with a protectinggroup.
 6. A compound according to claim 5 wherein the protecting groupis selected from the group consisting of Fmoc, benzyl,tert-butoxycarbonyl, benzyloxycarbonyl and (C₁-C₄) alkanoyl.
 7. A methodfor the prevention or treatment of a disease which may be prevented ortreated by modulating the effects of chemokines, in a patient in needthereof, comprising administering to such patient an effective dose of acompound of formula (I):

wherein: R₁ represents a hydrogen or halogen atom or a (C₁-C₄)alkyl,trifluoroethyl, hydroxyl, (C₁-C₄)alkoxy, trifluoromethoxy,trifluoroethoxy, (C₃-C₈)cycloalkyloxy, allyloxy, cyclopropylmethoxy or(C₁-C₄)alkylthio group; R₂ represents a hydrogen or halogen atom or a(C₁-C₈)alkyl, trifluoroethyl, perfluoro(C₁-C₄)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, (C₁-C₈)alkoxy, trifluoromethoxy, trifluoroethoxy, allyloxy,(C₃-C₈)cycloalkylmethoxy, (C₃-C₈)cycloalkyloxy or (C₃-C₈)cycloalkylmethyl group; R₃ represents —O—(C₂-C₄)alk-A, —O—(C₁-C₄)alk-B,—O-E, —(C₁-C₄)alk-A, —B, —(C₁-C₄)alk-NR₄—(C₂-C₃)alk-A,—(C₁-C₄)alk-NR₄—(C₁-C₃)alk-B, —CONR₄—(C₂-C₄)alk-A, —CONR₄—(C₁-C₄)alk-B,—CONR₄-E, —CO-D-(C₁-C₂)alk-A, —CO-G-A,

R₄ represents a hydrogen atom or a (C₁-C₄)alkyl group; A represents agroup NR₅R₆; B represents a group

D represents a group

E represents a group

G represents a group

R₅ and R₆ each represent, independently of each other, a hydrogen atomor a (C₁-C₆)alkyl, allyl, (C₂-C₄)alk-O—(C₁-C₄)alkyl, (C₂-C₄)alk-OH,(C₁-C₃)alk-CON(R₄)₂, (C₂-C₃) alk-NHCO—(C₁-C₄)alkyl, (C₃-C₇) cycloalkyl,(C₃-C₇) cycloalkylmethyl, —CO—(C₁-C₄)alkyl, benzyl, pyrrolidinyloptionally substituted with a —CO—(C₁-C₄)alkyl group, tetrahydropyranyl,tetrahydropyranylmethyl, dimethyltetrahydropyranyl, tetrahydrofuryl ortetrahydrofurylmethyl group; or R₅ and R₆, together with the nitrogenatom to which they are attached, constitute a heterocyclic radicalselected from the group consisting of aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, morpholinyl, piperazinyl,tropanyl, quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl, and2-aza-bicyclo[2,2,2]octanyl, the said heterocyclic radicals beingunsubstituted or substituted with a phenyl, halophenyl,trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy,hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino group, agroup —NR₄R₇, tetrahydropyran-4-ylamino, —CON(R₄)₂, —CONR₄R′₄,—CH₂CON(R₄)₂, (C₁-C₄)alkyl-CONR₄—, (C₃-C₈)cycloalkyl-CONR₄—,(C₁-C₄)alkyl-OCONR₄—, (C₃-C₈)cycloalkyl-OCONR₄—, ((C₁-C₄)alkyl-OCO)₂N—or (C₁-C₄)alkyl-COO—, or substituted with one or more methyl groups; R′₄represents a group (CH₂), linked to the carbon atom bearing —CONR₄R′₄;R₇ represents a hydrogen atom, a (C₁-C₄)alkyl or an —SO₂CH₃ group or R₄and R₇, together with the nitrogen atom to which they are attached,constitute a pyrrolidinyl or piperidinyl radical; p represents 1, 2, 3,4 or 5; q represents 0, 1 or 2; r represents 1 or 2; s represents 2 or3; p+q being less than or equal to 5; p+r being less than or equal to 5;and alk represents an alkylene; provided that R₁ and R₂ are notsimultaneously a hydrogen atom; or a pharmaceutically acceptable saltthereof.
 8. A method according to claim 7 wherein the disease is anacute or chronic immunoinflammatory disease or syndrome, allergicdisease, or a disease in which angiogenic processes are involved.
 9. Amethod according to claim 7 wherein the disease is atherosclerosis. 10.A method according to claim 7 wherein the disease is a viral orbacterial disease, cardiac pathology, or obesity.
 11. A method accordingto claim 7 wherein the compound is of formula (I′)

wherein: R₁ represents a hydrogen or halogen atom or a (C₁-C₄)alkyl,trifluoroethyl, hydroxyl, (C₁-C₄) alkoxy, trifluoromethoxy,trifluoroethoxy, (C₃-C₈)cycloalkyloxy, allyloxy, cyclopropylmethoxy or(C₁-C₄)alkylthio group; R₂ represents a hydrogen or halogen atom or a(C₁-C₈)alkyl, trifluoroethyl, perfluoro(C₁-C₄)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, (C₁-C₈)alkoxy, trifluoromethoxy, trifluoroethoxy, allyloxy,(C₃-C₈)cycloalkylmethoxy, (C₃-C₈)cycloalkyloxy or (C₃-C₈)cycloalkylmethyl group; R₃ represents —O—(C₂-C₄)alk-A, —O—(C₁-C₄)alk-B,—O-E, —(C₁-C₄)alk-A, —B, —(C₁-C₄)alk-NR₄—(C₂-C₃)alk-A,—(C₁-C₄)alk-NR₄—(C₁-C₃)alk-B, —CONR₄—(C₂-C₄)alk-A, —CONR₄—(C₁-C₄)alk-B,—CONR₄-E, —CO-D-(C₁-C₂)alk-A, —CO-G-A,

R₄ represents a hydrogen atom or a (C₁-C₄)alkyl group; A represents agroup NR₅R₆; B represents a group

D represents a group

E represents a group

G represents a group

R₅ and R₆ each represent, independently of each other, a hydrogen atomor a (C₁-C₆)alkyl, allyl, (C₂-C₄)alk-O—(C₁-C₄)alkyl, (C₂-C₄)alk-OH,(C₁-C₃)alk-CON(R₄)₂, (C₂-C₃)alk-NHCO—(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkylmethyl, benzyl, tetrahydropyranyl,tetrahydropyranylmethyl, dimethyltetrahydropyranyl, tetrahydrofuryl ortetrahydrofurylmethyl group; or R₅ and R₆, together with the nitrogenatom to which they are attached, constitute a heterocyclic radicalselected from the group consisting of aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, perhydroazepinyl, morpholinyl, piperazinyl,tropanyl, quinuclidinyl, 2-azabicyclo[2,2,1]heptanyl, and2-azabicyclo[2,2,2]-octanyl, the said heterocyclic radicals beingunsubstituted or substituted with a phenyl, halophenyl,trifluoromethylphenyl, trifluoromethyl, hydroxyl, methoxy,hydroxymethyl, methoxymethyl, formamido or trifluoroacetylamino group, agroup —NR₄R₇, tetrahydropyran-4-ylamino, —CON(R₄)₂, —CONR₄R′₄,—CH₂CON(R₄)₂, (C₁-C₄)alkyl-CONR₄—, (C₁-C₄)alkyl-OCONR₄— or(C₁-C₄)alkyl-COO—, or substituted with one or more methyl groups; R′₄represents a group (CH₂)_(s) linked to the carbon atom bearing—CONR₄R′₄; R₇ represents a hydrogen atom or a (C₁-C₄)alkyl or R₄ and R₇,together with the nitrogen atom to which they are attached, constitute apyrrolidinyl or piperidinyl radical; p represents 1, 2, 3, 4 or 5; qrepresents 0, 1 or 2; r represents 1 or 2; s represents 2 or 3; p+qbeing less than or equal to 5; p+r being less than or equal to 5; andalk represents an alkylene; provided that R₁ and R₂ are notsimultaneously a hydrogen atom; or pharmaceutically acceptable saltthereof.
 12. A method according to claim 7 wherein the compound is offormula (Ia)

or a pharmaceutically acceptable salt thereof.
 13. A method according toclaim 11 wherein the compound is of formula (Ia)

or a pharmaceutically acceptable salt thereof.
 14. A method according toclaim 12 wherein, in the compound of formula (Ia), R₁ represents ahalogen atom or a (C₁-C₄)alkyl, hydroxyl, (C₁-C₄) alkoxy, (C₃-C₈)cycloalkyloxy, allyloxy, cyclopropylmethoxy or (C₁-C₄)alkylthio group.15. A method according to claim 12 wherein, in the compound of formula(Ia), R₂ represents a halogen atom or a (C₁-C₈)alkyl, trifluoromethyl,(C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₈)alkoxy, allyloxy,(C₃-C₈)cycloalkylmethoxy, (C₃-C₈)cycloalkyloxy or (C₃-C₈)cycloalkylmethyl group.
 16. A method according to claim 12 wherein, inthe compound of formula (Ia), R₁ represents a halogen atom or a(C₁-C₄)alkyl, hydroxyl, (C₁-C₄) alkoxy, (C₃-C₈) cycloalkyloxy, allyloxy,cyclopropylmethoxy or (C₁-C₄) alkylthio group; R₂ represents a halogenatom or a (C₁-C₈)alkyl, trifluoromethyl, (C₃-C₁₀)cycloalkyl, phenyl,(C₁-C₈)alkoxy, allyloxy, (C₃-C₈)cycloalkylmethoxy, (C₃-C₈)cycloalkyloxyor (C₃-C₈)cycloalkylmethyl group; and R₃ represents —O—(C₂-C₄)alk-A,—O—(C₁-C₄)alk-B, —O-E, —(C₁-C₄)alk-A, —B, —(C₁-C₄)alk-NR₄—(C₂-C₃)alk-A,—(C₁-C₄)alk-NR₄—(C₁-C₃)alk-B, —CONR₄—(C₂-C₄)alk-A, —CONR₄—(C₁-C₄)alk-B,—CONR₄-E, —CO-D-(C₁-C₂)alk-A, —CO-G-A,


17. A method according to claim 16 wherein, in the compound of formula(Ia), R₁ represents a (C₁-C₄)alkoxy, cyclopropylmethoxy or(C₁-C₄)alkylthio group.
 18. A method according to claim 16 wherein, inthe compound of formula (Ia), R₂ represents a halogen atom or a(C₁-C₈)alkyl, trifluoromethyl, (C₃-C₁₀)cycloalkyl or (C₁-C₈)alkoxygroup.
 19. A method according to claim 16 wherein, in the compound offormula (Ia), R₃ represents —CO-G-A or —CONR₄—(C₁-C₄)alk-B.
 20. A methodaccording to claim 16, wherein, in the compound of formula (Ia), R₁represents a (C₁-C₄)alkoxy, cyclopropylmethoxy or (C₁-C₄)alkylthiogroup; R₂ represents a halogen atom or a (C₁-C₈)alkyl, trifluoromethyl,(C₃-C₁₀)cycloalkyl or (C₁-C₈)alkoxy group; and R₃ represents —CO-G-A or—CONR₄—(C₁-C₄)alk-B.